A Multi-center, Double-blind, Randomized, Placebo-controlled Study to Assess the Pharmacodynamics, Pharmacokinetics, Tolerability, and Safety of a Single Subcutaneous Injection of ACT-246475 in Adults With Stable Coronary Artery Disease
Phase: PHASE2
Conditions: Stable Coronary Artery Disease
Sponsor: Viatris Innovation GmbH

Protocol: ID-076A201 
A Multi-center, Double-blind, Randomized, Placebo-controlled Study to Assess the 
Pharmacodynamics, Pharmacokinetics, Tolerability, and Safety of a Single Subcutaneous 
Injection of ACT-246475 in Adults With Stable Coronary Artery Disease 
ClinicalTrials.gov Identifier: NCT03384966 

ACT-246475 
Coronary artery disease 
Protocol ID-076A201 
A multi-center, double-blind, randomized, placebo-controlled study to assess the 
pharmacodynamics, pharmacokinetics, tolerability, and safety of a single 
subcutaneous injection of ACT-246475 in adults with stable coronary artery disease 
Study Phase: 
2 
EudraCT Number: 
2017-003332-36 
Status and version: 
Version 1 
Date: 
31 August 2017 
Document type: 
Global Protocol 
Idorsia document number (Doc No.): 
D-17.029 
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Idorsia Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your personnel, and an independent ethics 
committee or institutional review board. It is understood that this information will not be disclosed to others 
without written authorization from Idorsia Pharmaceuticals Ltd, except to the extent necessary to obtain 
informed consent from those persons to whom the study treatment may be administered. 

ACT-246475 
Coronary artery disease 
Protocol ID-076A201 
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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 phone number:  
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File. 
SPONSOR CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Scientist 
 
Clinical Trial Statistician 
 
Clinical Trial Physician 
 
Clinical Trial Pharmacologist 
 
Drug Safety Physician 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
 
Department of Infection, Immunity & 
Cardiovascular Disease 
University of Sheffield 
 
 
Sheffield 
S10 2RX UK 
CONTRACT RESEARCH ORGANIZATIONS’ INFORMATION 
Some 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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ACT-246475 
Coronary artery disease 
Protocol ID-076A201 
Version 1 
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Confidential 
EudraCT 2017-003332-36 
Doc No D-17.029 
INVESTIGATOR SIGNATURE PAGE 
Study title 
A multi-center, double-blind, randomized, placebo-controlled study to assess the 
pharmacodynamics, pharmacokinetics, tolerability, and safety of a single subcutaneous 
injection of ACT-246475 in adults with stable coronary artery disease 
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 
subjects (other than those procedures necessary for the wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. 
Principal 
Investigator 

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Doc No D-17.029 
TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
SPONSOR CONTRIBUTORS TO THE PROTOCOL .......................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS’ INFORMATION ..................................2 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................11 
PROTOCOL SYNOPSIS ID-076A201 .............................................................................14 
1 
BACKGROUND .........................................................................................................23 
1.1 
Pre-hospital treatment of acute myocardial infarction .................................23 
1.2 
Role of adenosine diphosphate-induced platelet activation (P2Y12 
receptor) ........................................................................................................23 
1.3 
Study treatment (ACT-246475) ....................................................................25 
1.3.1 
Nonclinical data ................................................................................25 
1.3.2 
Effects in humans ..............................................................................26 
1.3.2.1 
Study AC-075-101 ..................................................................26 
1.3.2.2 
Study AC-076-101 ..................................................................26 
1.3.2.3 
Study AC-076-102 ..................................................................27 
1.4 
Purpose and rationale of the study ................................................................28 
1.5 
Summary of known and potential risks and benefits ....................................28 
1.5.1 
Potential risks related to study treatment administration ..................28 
1.5.2 
Potential risks associated with study-specific procedures ................29 
1.5.3 
Potential risk of unblinding ...............................................................30 
1.5.4 
Potential benefits ...............................................................................30 
1.5.5 
Overall benefit risk assessment .........................................................30 
2 
STUDY OBJECTIVES ...............................................................................................31 
2.1 
Primary objective ..........................................................................................31 
2.2 
Other objectives ............................................................................................31 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................31 
3.1 
Study design .................................................................................................31 
3.1.1 
Study periods ....................................................................................32 
3.1.2 
Study duration ...................................................................................33 
3.2 
Study design rationale ..................................................................................33 

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3.3 
Site personnel and roles ................................................................................34 
3.3.1 
Platelet aggregation technician .........................................................34 
3.4 
Study committees .........................................................................................35 
4 
SUBJECT POPULATION ..........................................................................................35 
4.1 
Subject population description .....................................................................35 
4.2 
Rationale for the selection of the study population ......................................35 
4.3 
Inclusion criteria ...........................................................................................36 
4.4 
Exclusion criteria ..........................................................................................36 
4.5 
Criteria for women of childbearing potential ...............................................38 
4.5.1 
Definition of childbearing potential ..................................................38 
4.5.2 
Acceptable methods of contraception ...............................................38 
5 
TREATMENTS ..........................................................................................................38 
5.1 
Study treatment .............................................................................................38 
5.1.1 
Investigational treatment and matching placebo: Description 
and rationale ......................................................................................38 
5.1.2 
Study treatment supply .....................................................................39 
5.1.2.1 
Study treatment packaging and labeling .................................39 
5.1.2.2 
Study treatment distribution and storage .................................39 
5.1.2.3 
Study treatment return and destruction ...................................40 
5.1.3 
Study treatment assignment and dispensing .....................................41 
5.1.3.1 
Study treatment assignment .....................................................41 
5.1.3.2 
Study treatment dispensing .....................................................41 
5.1.4 
Study treatment preparation and administration ...............................41 
5.1.5 
Blinding ............................................................................................42 
5.1.6 
Unblinding ........................................................................................43 
5.1.6.1 
Unblinding for final analyses ..................................................43 
5.1.6.2 
Unblinding for interim analyses ..............................................43 
5.1.6.3 
Unblinding for suspected unexpected serious adverse 
reactions ...................................................................................43 
5.1.6.4 
Emergency procedure for unblinding ......................................43 
5.1.7 
Study treatment accountability and compliance with study 
treatment ...........................................................................................44 
5.1.7.1 
Study treatment accountability ................................................44 
5.1.7.2 
Study treatment compliance ....................................................44 
5.1.8 
Study treatment dose adjustments and interruptions ........................44 
5.1.9 
Premature discontinuation of study treatment ..................................44 
5.1.10 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................44 

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5.2 
Previous and concomitant therapy ................................................................44 
5.2.1 
Definitions ........................................................................................44 
5.2.2 
Reporting of previous/concomitant therapy in the case report 
form ...................................................................................................45 
5.2.3 
Allowed concomitant therapy ...........................................................45 
5.2.4 
Forbidden concomitant therapy ........................................................45 
6 
STUDY ENDPOINTS ................................................................................................45 
6.1 
Efficacy endpoints ........................................................................................45 
6.2 
Pharmacokinetic and pharmacodynamic endpoints .....................................46 
6.2.1 
Pharmacodynamic endpoints ............................................................46 
6.2.2 
Pharmacokinetic endpoints ...............................................................46 
6.3 
Safety endpoints ...........................................................................................46 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................46 
7.1 
Study visits ...................................................................................................46 
7.1.1 
Screening/re-screening ......................................................................47 
7.1.2 
Unscheduled visits ............................................................................47 
7.2 
Study assessments .........................................................................................50 
7.2.1 
Demographics / baseline characteristics ...........................................50 
7.2.2 
Efficacy assessments .........................................................................51 
7.2.3 
Pharmacokinetic and pharmacodynamic assessments ......................51 
7.2.3.1 
Pharmacodynamic assessments ...............................................51 
7.2.3.2 
Pharmacokinetic assessments ..................................................52 
7.2.4 
Safety assessments ............................................................................53 
7.2.4.1 
Physical examination ...............................................................53 
7.2.4.2 
Vital signs ................................................................................53 
7.2.4.3 
Weight and height ...................................................................53 
7.2.4.4 
ECG assessment ......................................................................53 
7.2.5 
Laboratory assessments ....................................................................54 
7.2.5.1 
Type of laboratory ...................................................................54 
7.2.5.2 
Laboratory tests .......................................................................55 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................56 
8.1 
Study completion ..........................................................................................56 
8.2 
Premature withdrawal from study ................................................................56 
8.3 
Premature termination or suspension of the study ........................................57 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................57 

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9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................57 
9.1 
Adverse events ..............................................................................................57 
9.1.1 
Definition of adverse events .............................................................57 
9.1.2 
Intensity of adverse events ................................................................58 
9.1.3 
Relationship to study treatment ........................................................59 
9.1.4 
Reporting of adverse events ..............................................................59 
9.1.5 
Follow-up of adverse events .............................................................59 
9.2 
Serious adverse events ..................................................................................59 
9.2.1 
Definitions of serious adverse events ...............................................59 
9.2.2 
Reporting of serious adverse events .................................................60 
9.2.3 
Follow-up of serious adverse events .................................................61 
9.2.4 
After the 30-day follow-up period ....................................................61 
9.3 
Pregnancy .....................................................................................................61 
9.3.1 
Reporting of pregnancy ....................................................................61 
9.3.2 
Follow-up of pregnancy ....................................................................62 
9.4 
Study safety monitoring ................................................................................62 
10 STATISTICAL METHODS .......................................................................................62 
10.1 
Analysis sets .................................................................................................62 
10.1.1 
Screened analysis set ........................................................................62 
10.1.2 
Randomized analysis set ...................................................................62 
10.1.3 
Full analysis set .................................................................................62 
10.1.4 
Per-protocol analysis set ...................................................................63 
10.1.5 
Safety set ...........................................................................................63 
10.1.6 
Pharmacokinetic analysis set ............................................................63 
10.1.7 
Usage of the analysis sets .................................................................63 
10.2 
Variables .......................................................................................................64 
10.2.1 
Primary efficacy variable(s) ..............................................................64 
10.2.2 
Key secondary efficacy variables .....................................................64 
10.2.3 
Safety variables .................................................................................64 
10.2.3.1 
Adverse events ........................................................................64 
10.2.3.2 
Laboratory data ........................................................................65 
10.2.3.3 
ECG .........................................................................................65 
10.2.3.4 
Vital signs ................................................................................65 
10.2.4 
Pharmacokinetic and pharmacodynamic variables ...........................65 
10.2.4.1 
Pharmacokinetic variables .......................................................65 
10.2.4.2 
Pharmacodynamic variables ....................................................66 
10.3 
Description of statistical analyses .................................................................66 
10.3.1 
Overall testing strategy .....................................................................66 
10.3.2 
Analysis of the primary pharmacodynamic variable ........................67 

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10.3.2.1 
Hypotheses and statistical model ............................................67 
10.3.2.2 
Handling of missing data .........................................................68 
10.3.2.3 
Main analysis ...........................................................................68 
10.3.2.4 
Supportive/sensitivity analyses ...............................................69 
10.3.3 
Analysis of key secondary efficacy variable(s) ................................69 
10.3.4 
Analysis of the safety variables ........................................................69 
10.3.4.1 
Adverse events ........................................................................69 
10.3.4.2 
Laboratory data ........................................................................70 
10.3.4.3 
Vital signs, weight and physical examination .........................70 
10.3.4.4 
Electrocardiograms ..................................................................70 
10.4 
Interim analyses ............................................................................................70 
10.5 
Sample size ...................................................................................................70 
11 DATA HANDLING ....................................................................................................71 
11.1 
Data collection ..............................................................................................71 
11.2 
Maintenance of data confidentiality .............................................................72 
11.3 
Database management and quality control ...................................................72 
12 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................73 
12.1 
Ethics and Good Clinical Practice ................................................................73 
12.2 
Independent Ethics Committee / Institutional Review Board ......................73 
12.3 
Informed consent ..........................................................................................74 
12.4 
Compensation to subjects and investigators .................................................75 
12.5 
Protocol adherence/compliance ....................................................................75 
12.6 
Protocol amendments ...................................................................................75 
12.7 
Essential documents and retention of documents .........................................75 
12.8 
Monitoring ....................................................................................................77 
12.9 
Investigator Site File .....................................................................................78 
12.10 
Audit .............................................................................................................78 
12.11 
Inspections ....................................................................................................78 
12.12 
Reporting of study results and publication ...................................................79 
13 REFERENCES ............................................................................................................80 

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LIST OF TABLES 
Table 1 
Preparation of study treatment for subcutaneous administration ....................42 
Table 2 
Visit and assessment schedule. .......................................................................48 
Table 3 
Time points of main study assessments. .........................................................49 
Table 4 
Analysis datasets .............................................................................................64 
LIST OF FIGURES 
Figure 1 
Randomization scheme ...................................................................................32 
Figure 2 
Study design ....................................................................................................33 

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LIST OF ABBREVIATIONS AND ACRONYMS 
ACS 
Acute coronary syndrome 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
AMI 
Acute myocardial infarction 
AUC 
Area under the plasma concentration-time curve 
AUC0–24h 
Area under the plasma concentration-time curve from time zero to 
24 h time point 
BP 
Blood pressure 
CAD 
Coronary artery disease 
CFR 
Code of Federal Regulations (US) 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CRA 
Clinical research associate 
CRF 
(Electronic) case report form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTT 
Clinical trial team 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DAPT 
Dual antiplatelet therapy 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic acid 
eGFR 
Estimated glomerular filtration rate 
EOS 
End-of-Study 
FAS 
Full analysis set 
g 
Gravitational constant 
GCP 
Good Clinical Practice 
HA 
Health authority 
i.v.
Intravenous(ly) 
IB
Investigator’s Brochure 

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ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IPA 
Inhibition of platelet aggregation 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigator Site File 
LTA 
Light transmission aggregometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MTD 
Maximum tolerated dose 
OATP 
Organic anion-transporting polypeptide 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PPACK 
Phenylalanine-proline-arginine-chloromethyl ketone 
PPS 
Per-protocol set 
PRP 
Platelet-rich plasma 
PRU 
P2Y12 reaction units 
QA 
(Sponsor) Quality Assurance 
QS 
(Sponsor) Quality System 
QTcB 
QT corrected with Bazett’s formula 
QTcF 
QT corrected with Fridericia’s formula 
RND 
Randomized analysis set 
RSI 
Reference safety information 
s.c.
Subcutaneous 
s.l.
Sublingual 
SAD 
Single-ascending dose 
SAE 
Serious adverse event 

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SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SIV 
Site initiation visit 
SmPC 
Summary of Product Characteristics 
SS 
Safety set 
STEMI 
ST-segment elevation myocardial infarction 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
tmax 
Time to reach maximum plasma concentration 
TMF 
Trial Master File 

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PROTOCOL SYNOPSIS ID-076A201 
TITLE 
A multi-center, double-blind, randomized, placebo-controlled 
study to assess the pharmacodynamics, pharmacokinetics, 
tolerability, and safety of a single subcutaneous injection of 
ACT-246475 in adults with stable coronary artery disease. 
OBJECTIVES 
Primary objective(s) 
The primary objective of the study is to characterize inhibition 
of platelet aggregation (IPA) relatively to placebo after a single 
subcutaneous (s.c.) injection of ACT-246475 either in the thigh 
or in the abdomen at 2 different doses in subjects with stable 
coronary 
artery 
disease 
(CAD) 
receiving 
conventional 
background oral antiplatelet therapy (e.g., acetylsalicylic acid, 
P2Y12 receptor antagonists). 
Other objectives 
The other objectives of this study are described in Section 2.2. 
DESIGN 
This is a prospective, multi-national, multi-center, double-blind, 
randomized, 
placebo-controlled, 
parallel-group, 
Phase 2, 
exploratory study of a single s.c. administration of ACT-246475, 
at 2 different dose levels, in subjects with stable CAD receiving 
conventional background therapy (e.g., acetylsalicylic acid, 
P2Y12 receptor antagonists, etc.). 
Approximately 324 adult subjects with stable CAD will be 
randomized into 1 of the 8 combinations of the treatment, dose, 
and injection site using a 2:2:2:2:1:1:1:1 ratio: 

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Each subject will receive a single s.c. administration of either 
8 mg ACT-246475, 16 mg ACT-246475 or matching placebo, 
either in the thigh or in the abdomen. 
Double-blinding will apply to treatment (ACT-246475 vs 
placebo). The dose (8 mg vs 16 mg) will be single blinded 
(subject blinded). The injection site (thigh vs abdomen) will not 
be blinded. 
Treatment group allocation will be stratified based on baseline 
platelet reactivity value (expressed as P2Y12 reaction units 
[PRU]) measured on Day 1 by the VerifyNow® assay before 
ACT-246475 injection considering the 3 following categories: 
high 
reactivity 
(PRU > 250), 
medium 
reactivity 
(150 ≤ PRU ≤ 250), and low reactivity (PRU < 150). 
The study comprises the following consecutive periods: 
Screening period: Lasts 1 to 21 days; starts with the signature 
of the informed consent form and ends on Day −1. 
Treatment period: Lasts 2 days: Day 1 and Day 2. 
Follow-up period: Lasts 28 to 35 days. Starts on Day 3 and 
ends with the safety follow-up telephone call. 
PLANNED DURATION 
Approximately 7 months from first subject, first visit to last 
subject, last visit. 

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SITE(S) 
/ COUNTRY(IES) 
Approximately 20 sites in 5–10 countries are planned. 
INCLUSION CRITERIA 
1.
Signed informed consent prior to any study-mandated
procedure.
2.
Male and female subjects aged from 18–85 years,
inclusive.
3.
For women of childbearing potential: Negative urine
pregnancy test at Visit 1 and at Visit 2 before
randomization.
4.
Stable CAD defined by the presence of any of the
following conditions:
a.
History of CAD with coronary artery stenosis on coronary
angiogram ≥ 50%.
b. Previously documented myocardial infarction occurring
more than 3 months prior to randomization.
5.
Antiplatelet background therapy stable for at least
1 month prior to randomization.
6.
Body weight ≥ 40.0 kg (88.2 lbs).
EXCLUSION CRITERIA Conditions associated with atherosclerosis: 
1. Acute 
coronary 
syndrome, 
percutaneous 
coronary
intervention or any intervention for peripheral artery disease
within 3 months prior to randomization.
2. Acute ischemic stroke or transient ischemic attack within
3 months prior to randomization.
Mitigation of bleeding risks: 
3. Active internal bleeding, or medical history of recent
(< 1 month) bleeding disorders or conditions associated with
high 
risk 
of 
bleeding 
(e.g., clotting 
disturbances,
gastrointestinal bleed, hemoptysis).
4. Hemoglobin ≤ 10 g/dL at screening.
5. Loss of at least 250 mL of blood within 3 months of
screening.
6. Use of anticoagulants (oral, parenteral) or fibrinolytic
therapy within 24 h prior to screening (Visit 1).
7. Known 
platelet 
disorders 
(e.g., 
thrombasthenia,
thrombocytopenia, von Willebrand disease).

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Conditions that may prevent subject from complying with 
study requirements or may be a confounder for the study 
interpretation: 
8. Pregnant or breastfeeding women.
9. Uncontrolled hypertension according to investigator’s
judgment.
10. Known and documented moderate or severe hepatic
impairment.
11. End-stage renal failure requiring dialysis.
12. Any clinically significant findings on a physical exam, or
laboratory tests prior to screening that in the investigator’s
judgment would preclude safe or reliable participation of a
subject in the study.
13. Concomitant diseases (e.g., advanced liver cirrhosis, mental
illness, neurodegenerative disease, terminal malignancy,
etc.) or conditions (e.g., inability to communicate well with
the investigator in the local language) that, in the opinion of
the investigator, may prevent subject from complying with
study requirements or may be a confounder for the study
interpretation.
14. Veins unsuitable for intravenous puncture on either arm
(e.g., difficult to locate, access, or puncture) according to the
investigator’s judgment.
15. Clinically relevant skin disease that prevents s.c. injection in
the thigh or abdomen, according to the investigator’s
judgment.
16. Use of inhibitors of organic anion-transporting polypeptide
(OATP)1B1 or OATP1B3 at screening (Visit 1).
17. Known hypersensitivity to ACT-246475, any of its
excipients, or drugs of the P2Y12 class.
18. Previous exposure to investigational drug within 3 months
prior to screening.
STUDY TREATMENTS 
Investigational treatment and matching placebo 
Study treatment for s.c. administration will be available as 
sealed glass vials in 1 strength: 20 mg. The vials contain 22 mg 
of 
lyophilized 
ACT-246475A 
(hydrochloride 
salt 
of 
ACT-246475) or matching placebo to be reconstituted with 

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1 mL of water for injection. Further dilution with 1 mL NaCl 
0.9% will be performed for preparation of the dose of 8 mg. The 
s.c. formulation contains mannitol as an inactive ingredient.
Study treatment will be given as a single dose of ACT-246475 
(8 or 16 mg) or of matching placebo in a volume of 0.8 mL, 
administered s.c. at site by qualified personnel (e.g., nurse, 
physician). 
The investigational treatment and its matching placebo are 
indistinguishable, and all treatment kits will be packaged in the 
same way. 
CONCOMITANT 
THERAPY 
Allowed concomitant therapy 
Unless medically necessary, subjects will continue their standard 
treatment(s) (including oral P2Y12 receptor antagonists and 
acetylsalicylic acid) as prescribed (treatments and doses), from 
Visit 1 (screening) and up to the last PK or PD blood sample 
collection (whichever is latest). 
Forbidden concomitant therapy 
The following medications are prohibited from screening and up 
to last pharmacokinetic (PK) or pharmacodynamic (PD) blood 
collection (whichever is latest): 
•
Fibrinolytic therapy (e.g., streptokinase, alteplase, etc.)
•
Anticoagulants (e.g., Coumadin, warfarin, anti Xa inhibitors,
dabigatran, heparin)
•
OATP1B1 and OATP1B3 inhibitors (e.g., cyclosporine,
eltrombopag, lapatinib, lopinavir, rifampin, ritonavir)
Initiation of any of the following medications is prohibited from 
screening up to last PK or PD blood collection (whichever is 
latest): 
•
Oral P2Y12 receptor antagonists (e.g., clopidogrel, prasugrel,
ticagrelor)
•
Cangrelor

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ENDPOINTS 
Primary efficacy endpoint(s) 
Not applicable 
Pharmacodynamic endpoints 
The primary PD endpoint is the PD response that is defined for 
each subject as a PRU < 100 starting 30 minutes after injection 
and lasting for at least 3 hours, as measured via the VerifyNow® 
assay. 
This 
corresponds 
to 
inhibition 
of 
adenosine 
diphosphate-induced platelet aggregation (IPA) > 80%. 
Safety endpoints 
The safety endpoints will be assessed up to End-of-Study: 
•
Treatment-emergent adverse events (AEs) and serious AEs
(SAEs).
•
All AEs and SAEs.
•
Change in vital signs (systolic and diastolic arterial blood
pressure and pulse rate) from baseline to all assessed time
points during the study.
•
Treatment-emergent ECG abnormalities.
•
Change from baseline to each measured time point in ECG
variables: heart rate and the intervals: PQ/PR, QRS, QT, RR,
QT corrected with Bazett’s formula, QT corrected with
Fridericia’s formula.
•
Change from baseline to each measured time point for
clinical laboratory tests.
•
Treatment-emergent marked laboratory abnormalities.
Pharmacokinetic endpoints 
PK endpoints are described in Section 6.2.2. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 2 and Table 3. 
STATISTICAL 
METHODOLOGY 
Analysis sets 
The Screened analysis set includes all subjects who are screened 
and have a subject identification number. 
The Randomized analysis set includes all subjects who have 
been assigned to a double blind study treatment. 
The Full analysis set (FAS) includes all randomized subjects 

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who have been administered the study treatment. 
The Per-protocol set includes all FAS subjects who complied 
with protocol sufficiently to allow adequate estimation of the 
treatment effects (criteria for sufficient compliance will be 
detailed in the statistical analysis plan). 
The Safety set includes all subjects who received at least 1 dose 
of study treatment.  
The PK analysis set includes all Safety set subjects who have at 
least 1 PK sample collected after administration of study 
treatment. 
Primary analysis 
The analysis of the primary endpoint will be performed on the 
FAS comparing each active treatment dose to placebo using a 
2-sided z-test at type I error level of 0.025 (corresponding to an
overall level of 0.05 adjusted for multiplicity through Bonferroni
method). For each active treatment arm for which comparison to
placebo is statistically significant, the hypothesis that a
proportion of patients achieving a response is greater than 70%
will be tested at a 0.025 type I error level.
The study will be declared positive with regard to the primary 
objective arm if, for at least 1 of the 2 active treatment arms, the 
2 above-described tests are sequentially rejected. 
Additionally, longitudinal analysis of the treatment effect, from 
start of treatment up to 8 h after injection, on platelet reactivity 
as measured by VerifyNow®, i.e., PRU value, will be performed 
using a mixed model with PRU as dependent variable, subject as 
random factor, and treatment (8 mg, 16 mg, and placebo), 
injection site (abdomen, thigh), PRU level at randomization 
(stratification levels), age (continuous), gender (male, female), 
and assessment time (continuous) as fixed factors. The model 
will also include (treatment × injection site) as an interaction 
term to assess consistency of treatment effect across injection 
sites. 
A logistic regression analysis of the PD response will be 
performed using the same factors as covariates. 

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Summary of PD response, in terms of number (%) of subjects, 
will be provided. IPA as measured by VerifyNow® will also be 
summarized as a continuous variable. 
Supportive/sensitivity analyses 
Consistency across the following subgroups will be assessed by 
repeating the primary endpoint analysis, assuming relevant 
number of subjects: 
•
Age: < 55 vs ≥ 55 years
•
Body mass index: < 25.0 vs (≥ 25.0 and < 30.0)
vs ≥ 30.0 kg/m2
•
Sex: male vs female
•
Diabetes mellitus at baseline: yes vs no
•
Chronic kidney disease: yes vs no
Additional analyses of the supportive PD endpoint (light 
transmission aggregometry-based PD response) will be 
conducted using the same approach as described for the primary 
PD analysis. 
Sample size 
The primary objective is to assess the effectiveness of 
ACT-246475 to allow subjects to achieve a predefined PD 
response; therefore, the sample size provided is sufficient to 
sequentially demonstrate that at least 1 of the 2 ACT-246475 
doses has a higher response rate than placebo and that this 
response rate is greater than 70%. 
The sample size required for demonstrating a difference to 
placebo, based on an overall type I error of 0.05 (2-sided), 
adjusted for multiplicity using a Bonferroni method to 0.025 for 
each comparison, a power of 90%, a response rate of 50% under 
H0 (placebo) and 75% under H1 is 96 per arm. 
The sample size required to demonstrate that the response rate is 
different from 70% is based on a 2-sided type I error of 0.025, a 
power of 90%; and the assumptions of a response rate of 70% 
under H0 and 85% under H1 is 98 per arm. 
The study should include at least 98 subjects in each treatment 
arm, and assuming a rate of drop-out or non-evaluable data of 

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about 10%, 108 subjects should be included in each arm, giving 
a total of 324 subjects enrolled in the study. 
STUDY COMMITTEES 
A Safety Event Committee will consist of 2 independent clinical 
experts who will review unblinded safety data independently 
from the sponsor during the study. The Safety Event Committee 
has overall responsibility for safeguarding the interests of 
subjects by monitoring safety data obtained in the study and 
making appropriate recommendations based on the reported 
data. The Safety Event Committee will be fully operational prior 
to enrollment of the first subject into the study. 
The Safety Event Committee will specifically focus on 
study-drug-related clinically relevant major bleeding events, 
according to the Thrombolysis in Myocardial Infarction 
definition, that occur within the first 3 days after dosing. 

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PROTOCOL 
1 
BACKGROUND 
1.1 Pre-hospital treatment of acute myocardial infarction 
Despite marked improvement of in-hospital management of patients with acute 
myocardial infarction (AMI) in the past decades, there is still a medical need for an 
earlier treatment option to reduce high platelet reactivity, once a secondary event occurs 
[Nabel 2012]. The median time to medical intervention in economically advanced 
countries, either in an ambulance or at the emergency department, is still 2–4 hours after 
onset of symptoms, with patient decision time contributing significantly to the 
pre-hospital time delay [Garofalo 2012, Tubaro 2011]. 
Patients experiencing an AMI have highly reactive platelets, which are insufficiently 
inhibited even when they are receiving dual antiplatelet therapy (DAPT) with 
acetylsalicylic acid and clopidogrel [Gurbel 2003; Matetzky 2004; Wang 2010]. 
The earlier one intervenes on the ongoing platelet-rich thrombus responsible for AMI, the 
higher the chance to avoid early death and irreversible myocardial damage. The first 
1–3 hours after symptom onset (‘golden time’) hold the maximum potential for 
myocardial reperfusion and salvage in patients with ST-segment elevation myocardial 
infarction (STEMI) [Savonitto 2017]. Hence, shortening the time to treatment could be of 
therapeutic benefit. The European Society of Cardiology guidelines recommend 
ticagrelor and prasugrel as a first-line antiplatelet therapy on top of acetylsalicylic acid in 
AMI; however, evidence of their benefit in the pre-hospital setting is lacking 
[Beygui 2015]. 
ACT-246475 is being developed for self-injection in patients with suspected AMI. 
1.2 Role of adenosine diphosphate-induced platelet activation (P2Y12 
receptor) 
When vascular integrity is compromised, signals are generated that cause circulating 
platelets to adhere to the vessel wall, become activated, and aggregate, forming a plug 
that seals off the site of injury to prevent blood loss. Autopsy studies demonstrated that 
the same processes occur upon rupture of an atherosclerotic plaque and can lead to 
uncontrolled platelet thrombus formation and vessel occlusion [Davies 1986]. Inhibition 
of platelet activation and aggregation is recognized as an effective strategy for prevention 
of atherothrombotic events in patients with atherosclerotic disease in the coronary, 
peripheral, and cerebrovascular circulation [Davì 2007, Michelson 2010]. 
The adenosine diphosphate (ADP) receptor P2Y12 plays a critical role in platelet 
activation and aggregation [Andre 2003, Dorsam 2004]. Platelet activation is initially 

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triggered by the interaction of surface glycoproteins with components of the 
subendothelial matrix or ruptured atherosclerotic plaque and is amplified by the release of 
soluble mediators, which also recruit new platelets. One of the most important soluble 
mediators is ADP, which is an agonist at two G protein-coupled receptors, P2Y1 and 
P2Y12. Both P2Y1 and P2Y12 participate in the activation of integrin glycoprotein IIb/IIIa, 
which binds fibrinogen, creating the cross-linked aggregates that form the thrombus. 
Whereas P2Y1 is important for the initial activation at low levels of ADP, it appears that 
P2Y12 is required to amplify and sustain the responses leading to stable thrombus 
formation. 
The P2Y12 receptor is a validated target for treatment and secondary prevention of major 
adverse vascular events in patients with AMI, and early initiation of DAPT with 
acetylsalicylic acid and a P2Y12 receptor antagonist is recommended [O’Gara 2013, 
Amsterdam 2014]. The efficacy of clopidogrel, the most widely used P2Y12 receptor 
antagonist, is limited by its slow onset of action and variable platelet inhibition. The 
newer, irreversible P2Y12 receptor antagonist prasugrel achieves more pronounced 
inhibition of platelet aggregation (IPA) and shows superior efficacy compared with 
clopidogrel, but the reduced risk of ischemic events is accompanied by an increased risk 
of bleeding [Wiviott 2007]. The need to reduce bleeding risk is illustrated by post-hoc 
analyses of several anti-platelet clinical studies [Eikelboom 2006, Amlani 2010]. These 
analyses revealed that there is a strong association between major bleeding and mortality 
in AMI patients.  
P2Y12 receptor antagonists from the thienopyridine class, such as clopidogrel and 
prasugrel, are prodrugs converted to active metabolites that irreversibly bind and 
inactivate the P2Y12 receptor for the lifespan of the platelet. It was initially thought that 
antagonists that bind reversibly to the receptor, such as ticagrelor, are less likely to cause 
bleeding than those that cause irreversible blockade, possibly because receptors remain 
responsive to high local concentrations of ADP [van Giezen 2009, Becker 2010]. In the 
PLATO trial, ticagrelor demonstrated a significant reduction in the risk of death from 
vascular causes / myocardial infarction (MI) / stroke, without a significant increase in 
PLATO-defined major bleeding compared to clopidogrel [Wallentin 2009]. However, 
ticagrelor still significantly increased major bleeding not associated with coronary artery 
bypass surgery [Wallentin 2009, Husted 2011]. Therefore, novel principles of P2Y12 
antagonism are needed with the potential to improve efficacy without adversely affecting 
safety.  
Some of the bleeding associated with current P2Y12 receptor antagonists may be due to 
off-target effects. In a study comparing clopidogrel and prasugrel with genetic ablation of 
the P2Y12 receptor in mice, the thienopyridines caused excess bleeding and had adverse 
effects on vascular tone [Andre 2011]. In-house nonclinical studies indicate that 
ticagrelor, but not ACT-246475, inhibits vasoconstriction in isolated vessels 

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[ACT-246475 IB]. After vessel injury, vasoconstriction is essential to achieve hemostasis 
and subsequent wound sealing. Therefore, a highly selective P2Y12 receptor antagonist 
has the potential to provide an improved therapeutic window compared with current 
P2Y12 receptor antagonists. 
1.3 Study treatment (ACT-246475) 
ACT-246475 is a new, potent, reversible, and highly selective P2Y12 receptor antagonist 
with rapid onset and a short duration of action, suitable for subcutaneous (s.c.) 
administration. Efficacy and safety studies with ACT-246475 in animal thrombosis 
models suggest the potential for an improved therapeutic window in clinical use, 
compared with currently available oral agents. 
ACT-246475 is considered as a promising new agent for secondary prevention of major 
adverse cardiovascular events in patients with suspected AMI, including those 
undergoing percutaneous coronary intervention (PCI). 
1.3.1 Nonclinical data 
ACT-246475 is a potent and selective P2Y12 receptor antagonist. The binding of 
ACT-246475 to the receptor is fully reversible, with an equilibrium dissociation constant 
of 1.5 nM. In human platelet-rich plasma (PRP), ACT-246475 inhibited ADP-induced 
platelet aggregation with an inhibitor concentration causing 50% inhibition of 8.7 ng/mL 
(14 nM). 
ACT-246475 dose-dependently blocked thrombus formation in 2 species, guinea pig and 
rat. In the rat FeCl3 model, ACT-246475 was compared with ticagrelor, another 
reversible P2Y12 receptor antagonist. ACT-246475 displayed an improved safety window 
with respect to bleeding risk, based on surgical blood loss assessed at antithrombotic 
doses. For a given antithrombotic effect, blood loss was up to 2.6-fold less with 
ACT-246475 than with ticagrelor. In mechanistic studies using rat isolated femoral 
arteries, ticagrelor, but not ACT-246475, caused relaxation of precontracted arteries and 
inhibited vasoconstriction induced by electrical field stimulation or phenylephrine 
(α1-adrenoceptor-mediated). The absence of effect on vascular tone explains, at least in 
part, the reduction in bleeding with ACT-246475. 
 
 
 
 
 
 
 
 
 

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ACT-246475 has low potential for drug-drug interaction with co-medications dependent 
on cytochrome P450 (CYP) metabolism. ACT-246475 is not an activator of the human 
pregnane X receptor and CYP induction is, therefore, not expected upon dosing of 
ACT-246475.  
 
 
. 
 
Detailed information regarding nonclinical data is available in the Investigator’s 
Brochure (IB) [ACT-246475 IB]. 
1.3.2 Effects in humans 
Two clinical trials have been completed to date (AC-075-101, AC-076-101). Another 
trial is clinically completed with preliminary data available (AC-076-102). Results of 
these studies are detailed in the IB [ACT-246475 IB] and summarized hereafter. 
1.3.2.1 Study AC-075-101 
This study consisted of 2 parts: 
In Part I, the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of 
single, ascending, oral doses (5, 20, 80, 320, and 1000 mg) of the prodrug ACT-281959 
were assessed in 40 healthy, male subjects (n = 6/2 on active/placebo per dose level).  
In Part II, the safety, tolerability and PK of single, oral doses of prodrug formulations I 
and II (70 mg) and ACT-246475 (50 mg) were determined in 9 healthy, male subjects 
applying a 3-way crossover, open-label design.  
Each dose and formulation was safe and well tolerated. The systemic exposure to the 
active moiety ACT-246475 was generally low. Accordingly, the IPA was also limited. 
1.3.2.2 Study AC-076-101 
This was a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) 
study to investigate the safety, tolerability, PK and PD of ACT-246475 after s.c. 
administration to healthy male subjects. 
 
 
 
 

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1.3.2.3 Study AC-076-102 
This was a randomized, double-blind, placebo-controlled, SAD study to investigate the 
safety, tolerability, PK, and PD of ACT–246475 after s.c. (Part A) and sublingual 
(s.l.; Part B) administration to healthy male subjects.  
This study has been clinically completed and the database locked. The clinical study 
report (CSR) is not yet available. 
In Part A, there were a total of 48 subjects exposed (6 subjects receiving active treatment 
and 2 subjects receiving placebo per dose level). 
ACT–246475 has been determined to be safe and tolerated at each s.c. dose level ranging 
from 1 mg to 32 mg.  
The overall AE incidence was 12.5% (6 of 48 subjects exposed) with no indication of 
dose dependency. There were 5 of 36 subjects with AEs after administration of 
ACT-246475 (13.9%) vs 1 of 12 after placebo (8.3%). Each AE after administration of 
ACT–246475 was mild and transient. 
•
In the 2 mg dose group, 2 subjects reported 1 AE each (headache; dizziness) after
administration of ACT–246475.
•
In the 8 mg dose group, there were 3 subjects with at least 1 AE after administration
of ACT–246475 (rhinorrhea; headache; dizziness, nausea and hyperhidrosis).
•
One subject reported 3 AEs after administration of placebo (catheter site erythema,
nausea, and headache).
•
In the other dose groups (1 mg, 4 mg, 16 mg, and 32 mg), no AEs were reported.

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There were no deaths, SAEs, bleeding events, or AEs leading to discontinuation of the 
study. No clinically relevant changes in laboratory variables, vital signs, ECG variables, 
body weight, physical examination, or vigilance tests were observed. 
Peak plasma concentrations were reached within approximately 30–45 min and t½ ranged 
from 1.3–9.2 h. Exposure increased in a dose-proportional manner. 
At each dose level, peak IPA was achieved within approximately 15–30 min post-dosing. 
Peak %IPA exceeded 85% at doses ≥ 4 mg. The duration of PD effects was dose 
dependent. Mean 
%IPA ≥ 85% was sustained for approximately 6 h and 
12 h post-administration of 16 mg or 32 mg ACT–246475, respectively. 
In Part B, there were a total of 8 subjects exposed (6/2 on active/placebo). ACT-246475 
has been determined to be safe and tolerated after a single s.l. dose of 20 mg. 
Two subjects reported AEs after s.l. administration of ACT–246475: lightheadedness in 
1 subject and headache, vomiting, dizziness, and dyspepsia in the other subject. Neither 
of the 2 subjects exposed to placebo reported AEs. 
 
1.4 Purpose and rationale of the study 
ACT-246475 is a potent, short-acting, reversible, and selective antagonist of the platelet 
P2Y12 receptor, which is a validated target for the treatment and prevention of arterial 
thrombosis. ACT-246475 has shown a favorable PK/PD and safety profile in animal 
models, confirmed in studies conducted in healthy subjects. This Phase 2 study is 
conducted in subjects with atherosclerotic disease to generate data which are critical for 
dose selection in future clinical trials in the target AMI population. The impact of 
2 different doses and 2 different sites of injection (abdomen vs thigh) on the PD, PK, 
safety and tolerability of ACT-246475 will be assessed. 
1.5 Summary of known and potential risks and benefits 
1.5.1 Potential risks related to study treatment administration 
The main risks known to be associated with any P2Y12 receptor antagonist are related to 
an increased risk of bleeding events [Eikelboom 2006, Wiviott 2007, Amlani 2010].  
In nonclinical studies, ACT-246475 was found to have lower risk of bleeding compared 
to ticagrelor [Section 1.3.1]. This may be related to a different mechanism of action than 
that of ticagrelor: in contrast with ticagrelor, ACT-246475 has no interference with the 
adenosine pathway and ACT-246475 exhibits competitive inhibition of the 
P2Y12 receptor whereas inhibition by ticagrelor is non-competitive. More importantly, the 
risk of bleeding associated with the use of P2Y12 receptor antagonists increases with the 

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duration of treatment. As ACT-246475 has a short duration of action and is used as a 
single-dose administration, bleeding risk exposure is expected to be minimal in this 
study. The risks of bleeding are mitigated by exclusion of subjects who have active 
internal bleeding (exclusion criterion #3) or who are at high risk of bleeding: subjects 
with a history of recent bleeding disorder (exclusion criterion #3), subjects taking 
anticoagulants as background therapy (exclusion criterion #6), and subjects with known 
platelet disorders (exclusion criterion #7). 
In this study, the highest dose planned to be used is 16 mg, which is 2-fold lower than the 
highest dose administered in the AC-076-102 SAD study conducted in healthy subjects. 
In the AC-076-102 SAD study, headache was the most commonly reported AE 
[see Section 1.3.2.3]. There were no deaths, SAEs, bleeding events or AEs leading to 
discontinuation. No clinically relevant changes in laboratory variables, vital signs, ECG 
variables, body weight, physical examination, or vigilance tests were observed. 
Accordingly, s.c. administration of ACT-246475 has been determined to be safe and 
tolerated at each dose level ranging from 1 mg to 32 mg and, therefore, no MTD in 
humans has been defined. 
This study will be the first ACT-246475 study enrolling patients. Accordingly, an 
independent Safety Event Committee [Section 3.4] will have overall responsibility for 
safeguarding the interests of subjects by monitoring unblinded safety data (with specific 
focus on bleeding events occurring within 3 days of study treatment administration) and 
making appropriate recommendations based on the reported data, thus ensuring that the 
study is conducted to the highest scientific and ethical standards.
1.5.2 Potential risks associated with study-specific procedures 
The risks associated with the study-specific procedures are restricted to the standard risks 
associated with any blood collection. Such procedures are routine practice in the selected 
sites and, therefore, the risks are considered minimal for the subjects. The volume of 
blood collected for study purposes will be approximately 120 mL over a period of up to 
3 weeks, with a maximum of approximately 88 mL collected on a single day. To 
minimize the risks associated with the amount of blood collected, the minimum weight 
for a subject to be eligible has been set to 40 kg (inclusion criterion #6), and subjects with 
low hemoglobin at baseline (exclusion criterion #4) or significant recent blood loss 
(exclusion criterion #5) are excluded. For the subjects with a body weight between 
40 and 50 kg (88.2 and 110 lbs), the assessments requiring blood collection have been 
reduced: Light transmission aggregometry (LTA) platelet aggregation tests (supportive 
assessment) will not be performed in order to minimize the blood volume collected in 
these low-weight subjects. For these subjects, the total volume of blood collected for 
study purposes will be approximately 85 mL over a period of up to 3 weeks, with a 
maximum of approximately 58 mL collected on a single day. Overall, the blood volume 

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collected for study purposes will not exceed a maximum of approximately 3.5% of total 
blood volume over the 3-week study period and 2.5% of total blood volume over a single 
day. This is in compliance with the recommendations for maximum blood collection for 
research purposes from several Independent Ethics Committees or Institutional Review 
Boards (IECs/IRBs), and is therefore considered to represent a minimal risk for the 
subjects. 
1.5.3 Potential risk of unblinding 
Some study activities may potentially lead to unintentional unblinding. Performing the 
platelet aggregation tests may provide information that allows guessing of the actual 
treatment received (ACT-246475 or placebo). In order to limit the risks of unblinding, 
some study-specific roles for site personnel are defined and source documents will be 
kept separately [see Section 3.3]. 
The clinical research associates (CRAs) are considered unblinded [see Section 5.1.5] as 
they will have access to platelet aggregation test results. They will be in contact with the 
investigator and other site personnel who must remain blinded to these data. The CRA 
will be instructed to not communicate or discuss any platelet aggregation results except 
with the platelet aggregation technician. Accordingly, the risks of potential bias related to 
interaction between the CRA and site personnel are considered negligible. 
However, inadvertent access to potentially unblinding data (e.g., data gathered with 
VerifyNow® or LTA assays) may still happen. Because the primary endpoint is an 
objective PD endpoint, this is not considered critical for the study and for the reliability 
of the results. 
1.5.4 Potential benefits 
There is no expected direct health benefit for an individual subject participating in this 
study. However, this study is part of the development of a new treatment addressing an 
unmet medical need that may ultimately benefit the population of patients at high risk of 
AMI recurrence. On top of reimbursement of their study-related expenses, subjects 
participating to this study will get financial compensation for their time spent in the study 
in compliance with local regulations [see Section 12.4]. 
1.5.5 Overall benefit risk assessment 
Overall, due to the favorable safety profile of ACT-246475 as well as the use of routine 
standard procedures, the risks for subjects participating in this study are considered 
minimal and medically acceptable. 
It is the investigator’s responsibility to monitor the risk-benefit ratio of study treatment 
administration, as well as the degree of distress caused by study procedures on an 

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individual subject level, and to discontinue the study for a subject if, on balance, he/she is 
of the opinion that continuation would be detrimental to the subject’s well-being. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to characterize IPA relative to placebo after a single 
s.c. injection of ACT-246475 either in the thigh or in the abdomen at 2 different doses in
subjects with stable coronary artery disease (CAD) receiving conventional background
oral antiplatelet therapy (e.g., acetylsalicylic acid, P2Y12 receptor antagonists).
2.2 Other objectives 
The other objectives of this study, following a single s.c. administration of ACT-246475, 
are: 
•
To assess the PK of ACT-246475.
•
To assess the impact of the injection site location (thigh vs abdomen) on the PK and
PD of ACT-246475.
•
To investigate the impact of concomitant drug use, age, sex, and other covariates on
the PK and PD of ACT-246475.
•
To investigate the safety and tolerability of ACT-246475.
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-national, multi-center, double-blind, randomized, 
placebo-controlled, 
parallel-group, 
Phase 
2, 
exploratory 
study 
of 
a 
single 
s.c. administration of ACT-246475, at 2 different dose levels, in subjects with stable
CAD receiving conventional background therapy (e.g., acetylsalicylic acid, P2Y12
receptor antagonists, etc.).
Approximately 324 adult subjects with stable CAD will be randomized into 1 of the 
8 combinations of the treatment, dose, and injection site using a 2:2:2:2:1:1:1:1 ratio as 
described in Figure 1. 

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Figure 1 
Randomization scheme 
Each subject will receive a single s.c. administration of either 8 mg ACT-246475, 16 mg 
ACT-246475 or matching placebo, either in the thigh or in the abdomen. 
Treatment group allocation will be stratified based on baseline platelet reactivity value 
(expressed as P2Y12 reaction units [PRU]) measured on Day 1 by the VerifyNow® assay 
before ACT-246475 injection, considering the 3 following categories: high reactivity 
(PRU > 250), medium reactivity (150 ≤ PRU ≤ 250), and low reactivity (PRU < 150). 
No interim analysis is planned for this study. 
The study will be conducted at approximately 20 sites and in 5–10 countries (recruitment 
will be competitive across sites). The list of sites including the name and title of the 
investigators who are responsible for conducting the trial, and the address and telephone 
numbers of the trial sites will be filed in the Trial Master File (TMF). 
3.1.1 Study periods 
The study comprises the following consecutive periods: 
Screening period: Lasts 1–21 days; starts with the signature of the informed consent 
form (ICF) and ends on Day −1. 
Treatment period: Lasts 2 days: Day 1 and Day 2. 

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Follow-up period: Lasts 28–35 days (i.e., 30–37 days after single administration of 
study drug). Starts on Day 3 and ends with the safety follow-up telephone call. 
The visit schedule and protocol-mandated procedures will be performed according to the 
table of assessments [Table 2 and Table 3] and are described in Section 7. 
The overall study design is depicted in Figure 2. 
Figure 2 
Study design 
3.1.2 Study duration 
The study starts with the first act of recruitment (i.e., first ICF signed for the first subject) 
and ends with the last visit of the last subject. 
The overall duration of participation in the study (including screening and follow-up 
periods) for a subject will be up to 58 days. 
3.2 Study design rationale 
The study design supports the different study objectives, i.e., assessing PD, PK, 
tolerability, and safety profiles of ACT-246475. The treatment period is justified by the 
primary objective, which is to characterize the IPA after a single s.c. injection of 
ACT-246475, either in the thigh or in the abdomen, at 2 different doses in subjects with 
stable CAD. 

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The use of 2 doses (i.e., 8 and 16 mg) will allow assessment of the dose/PK and dose/PD 
relationship in this patient population, which will enrich the results already obtained in a 
healthy subject population [see Section 5.1.1 for detailed rationale on dose selection]. 
The stratification by baseline PRU value is implemented in order to account for different 
levels of P2Y12 inhibition at baseline. The boundaries have been selected to mimic the 
expected baseline level of P2Y12 receptor inhibition depending on the type of background 
antiplatelet therapy [Gurbel 2009]: PRU < 150; 150 ≤ PRU ≤ 250; PRU > 250. 
The primary PD analysis will be performed with the VerifyNow® method. Results from 
the VerifyNow® method are well correlated with those obtained with the LTA method 
[Varenhorst 2009, Gremmet 2015]. The VerifyNow® method has been preferred as it is 
more standardized than the LTA method; and therefore, less subject to variability in a 
multicenter study. In addition, the volume of blood required per sample is higher for LTA 
(6 mL) than for the VerifyNow® method (3 mL). Using the VerifyNow® method will 
allow assessment of more time points and, therefore, better characterization of the PD 
profile while requiring less blood withdrawn from the subjects. As LTA remains a 
reference method and to allow comparison with other trials, some LTA assessments will 
be performed at selected time points [Table 3]. 
The use of a double-blind placebo-controlled design is proposed to assess the safety of 
ACT-246475 compared with placebo and will support additional exploratory analyses. 
The double-blind design applies to the treatment allocation (i.e., ACT-246475 
vs placebo). The knowledge of the dose (8 or 16 mg) and injection site is not expected to 
affect the primary objective (which is based on objective PD assessment) or the safety 
evaluation as the study is placebo-controlled. However, to reduce the risks of bias in 
safety reporting, the dose will be blinded to the subjects (single blind). The injection site 
will not be blinded in this study. 
3.3 Site personnel and roles 
3.3.1 Platelet aggregation technician 
The technician(s) performing the platelet aggregation tests (VerifyNow® and LTA) will 
be considered unblinded to the treatment. They must not be involved in safety 
assessments and must not communicate with the results from the platelet aggregation 
tests to other study staff (only the stratification group will be communicated to the person 
in charge of randomization). 
To maintain the blind, the results of the platelet aggregation tests will be entered in the 
case report form (CRF) only by the technician and will not be accessible to other site 
study staff. Up to unblinding of the study, the source documents for platelet aggregation 
assays will be kept in a separate location from the subjects’ other source documents and 
will only be accessible to the platelet aggregation technician(s) and to the CRA. 

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3.4 Study committees 
A Safety Event Committee will consist of 2 independent clinical experts who will review 
unblinded safety data independently from the sponsor during the study. The Safety Event 
Committee has overall responsibility for safeguarding the interests of subjects by 
monitoring safety data obtained in the study and making appropriate recommendations 
based on the reported data. The Safety Event Committee will be fully operational prior to 
enrollment of the first subject into the study. 
The Safety Event Committee will specifically focus on study-drug-related clinically 
relevant major bleeding events, according to the Thrombolysis in Myocardial Infarction 
definition, that occur within the first 3 days after dosing. 
The Safety Event Committee will be ruled by a specific charter and recommendations 
made by the Safety Event Committee will be documented and archived in the TMF. 
4 
SUBJECT POPULATION 
4.1 Subject population description 
This study will enroll adult male and female subjects aged 18–85 years (inclusive) with 
stable CAD, as defined by a history of CAD with coronary artery stenosis ≥ 50% on 
coronary angiogram or previously documented MI occurring more than 3 months before 
randomization. 
Subjects with significant medical conditions (e.g., active internal bleeding, history of 
recent bleeding disorder, platelet disorders, subjects requiring dialysis) as well as subjects 
taking oral anticoagulants as background treatment are not eligible to enter the study. 
Eligible subjects must be able and willing to give informed consent for participation in 
the clinical study. 
4.2 Rationale for the selection of the study population 
The population enrolled is expected to reflect the general population of patients with 
CAD. 
Among these patients, those with prior MI are at higher risk of recurrent ischemic events 
[Fox 2008]. Such patients are treated with acetylsalicylic acid as life-long background 
therapy. In addition, the American College of Cardiology/American Heart Association 
and ESC guidelines for the management of patients with STEMI and non-STEMI 
recommend DAPT for the secondary prevention of recurrent ischemic events for up to 
1 year after the acute coronary syndrome (ACS) event, a duration that may be shortened 
or extended in selected patients if required [Steg 2012; O’Gara 2013; Amsterdam 2014; 
Roffi 2016; Levine 2016]. The target population for this study will include patients with 
coronary artery stenosis and patients who have experienced an AMI more than 3 months 

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prior to randomization. Those patients being candidates for single or DAPT according to 
guidelines, it is therefore expected to collect sufficient PD and safety data of 
ACT-246475 on top of antiplatelet therapy including a P2Y12 receptor antagonist. 
Ticagrelor and prasugrel are both expected to already provide more than 80% of IPA in 
patients who are compliant with their treatment [Prasugrel® SmPC, Ticagrelor® SmPC]. 
It cannot be excluded that, despite treatment with a potent oral P2Y12 receptor antagonist, 
some patients experiencing an MI still have high on-treatment platelet reactivity and may 
therefore benefit from ACT-246475. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject: 
1.
Signed informed consent prior to any study-mandated procedure.
2.
Male and female subjects aged from 18–85 years, inclusive.
3.
For women of childbearing potential: Negative urine pregnancy test at Visit 1 and
at Visit 2 before randomization.
4.
Stable CAD defined by the presence of any of the following conditions:
a.
History of CAD with coronary artery stenosis on coronary angiogram ≥ 50%.
b. Previously documented MI occurring more than 3 months prior to randomization.
5.
Antiplatelet background therapy stable for at least 1 month prior to
randomization.
6.
Body weight ≥ 40.0 kg (88.2 lbs).
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any subject: 
Conditions associated with atherosclerosis: 
1. ACS, PCI or any intervention for peripheral artery disease within 3 months prior to
randomization.
2. Acute ischemic stroke or transient ischemic attack (TIA) within 3 months prior to
randomization.
Mitigation of bleeding risks: 
3. Active internal bleeding, or medical history of recent (< 1 month) bleeding disorders
or conditions associated with high risk of bleeding (e.g., clotting disturbances,
gastrointestinal bleed, hemoptysis).

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4. Hemoglobin ≤ 10 g/dL at screeninga.
5. Loss of at least 250 mL of blood within 3 months of screening.
6. Use of anticoagulants (oral, parenteral) or fibrinolytic therapy within 24 h prior to
screening (Visit 1).
7. Known platelet disorders (e.g., thrombasthenia, thrombocytopenia, von Willebrand
disease).
Conditions that may prevent subject from complying with study requirements or 
may be a confounder for the study interpretation: 
8. Pregnant or breastfeeding women.
9. Uncontrolled hypertension according to investigator’s judgment.
10. Known and documented moderate or severe hepatic impairment.
11. End-stage renal failure requiring dialysis.
12. Any clinically significant findings on a physical exam, or laboratory tests prior to
screening that in the investigator’s judgment would preclude safe or reliable
participation of a subject in the study.
13. Concomitant 
diseases 
(e.g., 
advanced 
liver 
cirrhosis, 
mental 
illness,
neurodegenerative disease, terminal malignancy, etc.) or conditions (e.g., inability to
communicate well with the investigator in the local language) that, in the opinion of
the investigator, may prevent subject from complying with study requirements or may
be a confounder for the study interpretation.
14. Veins unsuitable for i.v. puncture on either arm (e.g., difficult to locate, access, or
puncture) according to the investigator’s judgment.
15. Clinically relevant skin disease that prevents s.c. injection in the thigh or abdomen,
according to the investigator’s judgment.
16. Use of inhibitors of organic anion-transporting polypeptide (OATP)1B1 or OATP1B3
at screening (Visit 1).
17. Known hypersensitivity to ACT-246475, any of its excipients, or drugs of the P2Y12
class.
18. Previous exposure to any investigational drug within 3 months prior to screening.
a If the results from the central laboratory for Visit 1 are available at time of randomization they must be used for 
assessment of eligibility. Otherwise, it is acceptable to assess this criterion based on local laboratory data from 
Visit 1 or more recent. 

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4.5 Criteria for women of childbearing potential 
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least 1 of the 
following criteria: 
•
Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy,
•
Postmenopausal (defined as 12 consecutive months with no menses without an
alternative medical cause [International council for harmonization (ICH) M3
definition]),
•
Premature ovarian failure (confirmed by a specialist), XY genotype, Turner
syndrome, uterine agenesis.
The reason for not being of childbearing potential will be recorded in the CRF. 
4.5.2 Acceptable methods of contraception 
Women of childbearing potential [see definition in Section 4.5.1] must use one of the 
following methods of birth control from Screening up to at least 30 days after study 
treatment administration: 
1.
Diaphragm / female condom / cervical cap / partner’s use of a condom.
2.
Intra-uterine devices.
3.
Oral or injectable contraceptive agents, implants, or transdermal contraceptive
hormone patches. If a hormonal contraceptive is chosen, it must be taken for at least
1 month prior to randomization.
4.
Sterilization method (tubal ligation / occlusion, or partner’s vasectomy).
5.
True abstinence from intercourse with a male partner only when this is in line with
the preferred lifestyle of the subject.
Rhythm methods are not considered as acceptable methods of contraception for this 
study. 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the CRF. 
5 
TREATMENTS 
5.1 Study treatment 
5.1.1 Investigational treatment and matching placebo: Description and rationale 
Study treatment for s.c. administration will be available as sealed glass vials in 1 strength: 
20 mg. The vials contain 22 mg of lyophilized ACT-246475A (hydrochloride salt of 

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ACT-246475) or matching placebo to be reconstituted with 1 mL of water for injection. 
The s.c. formulation contains mannitol as an inactive ingredient. 
Study treatment will be given as a single dose, administered s.c. at site by qualified 
personnel (e.g., nurse, physician). 
ACT-246475 at 2 different doses (8 and 16 mg) and placebo will be administered during 
this study. The ACT-246475 doses have been selected based on data from the SAD 
AC-076-102 study and on modeling to meet the following criteria: 
•
The low dose (8 mg) is the minimal dose achieving at least 85% IPA for 3 h which
corresponds to a time period during which complete suppression of platelet reactivity
is needed before specific in-hospital management of ACS [Montalescot 2014].
•
The high dose (16 mg) provides IPA of at least 85% in no more than 5% of the
subjects at 8 h. This corresponds to the maximal time accepted to limit interference
with invasive and/or pharmacological standard of care of AMI.
These 2 doses are considered distinct enough to allow further modeling of the optimal 
phase 3 dose based on study data. 
Note: onset of action of ACT-246475 is not dose-dependent and therefore did not account 
for dose selection. 
5.1.2 Study treatment supply 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local 
or national regulatory requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.2.1 Study treatment packaging and labeling 
Study treatment (ACT-246475 and matching placebo) will be provided in sealed glass 
vials as a lyophilizate to be reconstituted by a pharmacist or an authorized person as per 
local regulation. 
Study treatment will be labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.2.2 Study treatment distribution and storage 
The investigator is responsible for safe and proper handling and storage of the study 
treatment at the investigational site and for ensuring that the study treatment is 
administered only to subjects enrolled in the study and in accordance with the protocol. 

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5.1.2.2.1 Study treatment distribution 
The study centers will be supplied with study treatment according to the centers’ needs, 
depending on the rate of subject enrollment. Each center will have an individual stock of 
study treatment, which will be re-supplied continuously as soon as a predefined minimum 
number of study treatments have been reached.  
5.1.2.2.2 Study treatment storage 
Study treatment must be kept in a locked room or a locked cupboard in a restricted access 
room, which can be accessed only by the pharmacist, the investigator, or another duly 
designated person as specified on the delegation of authority form.  
 
 
A temperature log must be maintained and temperature check will have to occur at least 
on a weekly basis at the site. The sponsor/delegate will provide a temperature log; 
however, the use of the log is not mandatory if the site has an acceptable means of 
recording the temperature. Any temperature recording system routinely used at the site 
will be acceptable as long as all required information is included and certification of 
calibration is provided. If the temperature is captured electronically, a print-out will be 
made available to the CRA during each on-site visit. 
If a deviation from the approved temperature range is identified by the study center, the 
deviation must be reported to the CRA, preferably in writing and with supporting 
documentation (e.g., copy of the temperature log showing data for all excursion days). 
The CRA will immediately contact the sponsor for further advice. The affected study 
treatment must not be used (e.g., it will be segregated physically at the study center) until 
confirmation from the sponsor is obtained that its use is safe. If the temperature deviation 
is outside of the acceptable limit, the study treatment will be kept segregated at the study 
center and returned to the sponsor following internal study treatment return processes. 
New study treatment supplies will be provided to the study center. 
Temperature deviations correspondence must be kept in the Investigator Site File (ISF). 
5.1.2.3 Study treatment return and destruction 
On an ongoing basis and/or on termination of the study, the CRA will collect used and 
unused treatment kits, which will be returned to the warehouse. In certain circumstances, 
used and unused study treatment containers may be destroyed at the site once study 
treatment accountability is finalized, has been verified and reconciled by sponsor 
personnel or the deputy, and written permission for destruction has been obtained from 
the sponsor. Further details are provided in the study treatment handling manual. 

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5.1.3 Study treatment assignment and dispensing 
5.1.3.1 Study treatment assignment 
At Visit 2, after having verified that the subject meets all inclusion criteria and none of 
the exclusion criteria, and after performing the pre-dose VerifyNow® assessments, the 
platelet aggregation technician will provide the PRU stratification group to the person 
who will randomize the subject using the Interactive Response Technology (IRT) system. 
The IRT will assign a randomization number to the subject and will assign the treatment 
kit number as well as the dose and injection site, which matches the treatment arm 
assigned by the randomization list to the randomization number. 
The randomization list will be generated by an independent Contract Research 
Organization (CRO). 
5.1.3.2 Study treatment dispensing 
The IRT will allocate one treatment kit (1 vial) per subject at randomization. In the event 
of deviation from study treatment preparation instructions [Section 5.1.4] (e.g., breach of 
sterility conditions, incorrect dose), a new kit will be requested via the dispensing module 
of the IRT and preparation steps will be started again. The protocol-mandated study 
treatment dispensing procedures may not be altered without prior written approval from 
the sponsor. An accurate record of the date and amount of study treatment dispensed to 
each subject must be available for inspection at any time. 
5.1.4 Study treatment preparation and administration 
Detailed information about the study treatment preparation and stability of the solutions 
is provided within the study treatment handling manual. 
The preparation of the study treatment must be done under aseptic conditions by a 
pharmacist or an authorized person according to local regulation. 
The sealed glass vials containing the study treatment will be reconstituted with 1 mL of 
water for injection. The resulting stock solutions will be at a concentration of 20 mg/mL 
ACT-246475. For subjects randomized to receive the 8 mg dose of ACT-246475 or its 
matching placebo, dilution of the stock solution will be performed with 1 mL of NaCl 
0.9% to obtain the required concentration for injection [Table 1]. For all doses, the total 
volume administered will be 0.8 mL (i.e., concentration of the solutions adapted). 
The reconstituted ACT-246475 solution will be injected as s.c. single dose in the anterior 
mid-thigh skin or abdomen skin through 
 needle. The injected volume 
will be 0.8 mL for all subjects 
 
. 

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The protocol-mandated study treatment administration procedures may not be altered 
without prior written approval from the sponsor. An accurate record of the date and 
amount of study treatment administered to each subject must be available for inspection 
at any time. 
 
 
In Table 1, the preparation of doses of the study treatment is described; detailed 
instructions are given in the study treatment handling manual. 
The date and start time of preparation of the injection solution as well as the procedure 
must be recorded on source documents. 
Table 1 
Preparation of study treatment for subcutaneous administration 
Study 
treatment 
Dose 
Volume of 
water for 
injection 
Volume of 
NaCl 0.9% 
Stock solution 
concentration 
Aliquot of stock 
solution to be 
administered 
ACT-246475 
or placebo 
8 mg 
1 mL 
1 mL 
10 mg/mL 
0.8 mL 
ACT-246475 
or placebo 
16 mg 
1 mL 
-
20 mg/mL
0.8 mL 
5.1.5 Blinding 
This study will be performed in a double-blind fashion. The investigator, study personnel, 
subjects, sponsor personnel, and CRO personnel involved in the conduct of the study will 
remain blinded to the study treatment (ACT-246475 or placebo). 
The dose (8 mg or 16 mg) will be blinded only for the subject. The injection site (thigh or 
abdomen) will not be blinded. 
Sponsor staff responsible for clinical trial supply distribution will be partially unblinded 
at depot level to ensure adequate study oversight, but will remain blinded to subject 
randomization and subject treatment. 
Sponsor staff responsible for suspected unexpected serious adverse reaction (SUSAR) 
management may be unblinded to some subject treatment allocations. These persons will 
be clearly identified, their unblinding will be documented in the TMF and they will not 
take part in any Clinical Trial Team (CTT) meetings after study set-up has been 
completed. 

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The CRAs and the site technician performing the platelet aggregation assays will have 
access to the platelet aggregation test results (VerifyNow® and LTA) and will, therefore, 
be considered unblinded (they will not have access to the randomization list). 
The randomization list will be kept strictly confidential and accessible only to authorized 
persons, sponsor quality assurance (QA), and the PK analytical laboratory who are not 
involved in the conduct of the study, as long as the blinding needs to be maintained until 
final data analysis. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment kits will be packaged in the same way. 
5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after 
database closure, in accordance with the sponsor quality system (QS) documents. 
5.1.6.2 Unblinding for interim analyses 
Not applicable. 
5.1.6.3 Unblinding for suspected unexpected serious adverse reactions 
If a SUSAR occurs for a subject participating in the study, the sponsor’s Global Drug 
Safety department or a representative will request the unblinding of the treatment 
assignment. The treatment assignment will not be communicated to site personnel or to 
the sponsor CTT. Unblinded SUSAR information will be provided to respective HA and 
IECs or IRBs only. SUSARs will be reported to investigators in a blinded fashion. 
5.1.6.4 Emergency procedure for unblinding 
The investigator, study personnel, and sponsor personnel must remain blinded to the 
subject’s treatment assignment. The identity of the study treatment may be revealed only 
if the subject experiences a medical event, the management of which would require 
knowledge of the blinded treatment assignment. In this case, the investigator will receive 
the unblinded treatment assignment through the IRT. In these situations, the decision to 
unblind will reside solely with the investigator. Whenever it is possible, and if it does not 
interfere with (or does not delay) any decision in the best interest of the subject, the 
investigator will be invited to discuss the intended unblinding with sponsor personnel. 
The occurrence of any unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, sponsor personnel must be informed as soon as 
possible before or after the unblinding. 
The circumstances leading to unblinding must be documented in the ISF and CRF. 

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5.1.7 Study treatment accountability and compliance with study treatment 
5.1.7.1 Study treatment accountability 
The inventory of study treatment dispensed and returned (i.e., study-treatment 
accountability) must be performed by site personnel. It is to be recorded by site personnel 
on the study-treatment dispensing and accountability log and in the CRF, verified and 
reconciled by the CRA during the routine site visits and at the end of the study. The study 
treatment accountability in the CRF will include at least the following information for 
each study treatment unit (i.e., vial) dispensed to the subject: 
•
Dispensed vial number
•
Date vial dispensed
All study treatment supplies, including partially used or empty vials, must be retained at 
the site for review and reconciliation by the CRA. 
5.1.7.2 Study treatment compliance 
Study treatment compliance is based on administration of the study treatment as allocated 
by IRT. Any deviation from the randomization allocation will be reported as a protocol 
deviation. 
5.1.8 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments are not permitted. 
Study treatment interruptions are not applicable for this single-dose study. 
5.1.9 Premature discontinuation of study treatment 
Not applicable (single-dose study). 
5.1.10 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
Not applicable (single-dose study). 
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to signing of informed 
consent. 
A therapy that is study concomitant is any treatment that is ongoing or initiated after 
signing of informed consent, or initiated up to 30 days after study treatment 
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A therapy that is study treatment concomitant is any treatment that is either ongoing at 
the start of study treatment or is initiated up to 48 hours after study treatment 
administration. 
5.2.2 Reporting of previous/concomitant therapy in the case report form 
The use of all study concomitant therapy (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will be recorded 
in the CRF. 
Previous therapies related to subject’s underlying CAD will be recorded in the CRF if 
discontinued less than 1 month (≤ 30 days) prior to signing of the informed consent. 
The generic name, start/end dates of administration (as well as whether it was ongoing at 
start of treatment and/or End-of-Study [EOS]), route, dose, and indication will be 
recorded in the CRF. 
5.2.3 Allowed concomitant therapy 
Unless medically necessary, subjects will continue their standard treatment(s) (including 
oral P2Y12 receptor antagonists and acetylsalicylic acid) as prescribed (treatments and 
doses), from Visit 1 (screening) and up to the last PK or PD blood sample collection 
(whichever is latest). 
5.2.4 Forbidden concomitant therapy 
The following medications are prohibited from screening and up to last PK or PD blood 
collection (whichever is latest): 
•
Fibrinolytic therapy (e.g., streptokinase, alteplase, etc.)
•
Anticoagulants (e.g., Coumadin, warfarin, anti Xa inhibitors, dabigatran, heparin)
•
OATP1B1 and OATP1B3 inhibitors (e.g., cyclosporine, eltrombopag, lapatinib,
lopinavir, rifampin, ritonavir)
Initiation of any of the following medications is prohibited from screening up to last PK 
or PD blood collection (whichever is latest): 
•
Oral P2Y12 receptor antagonists (e.g., clopidogrel, prasugrel, ticagrelor)
•
Cangrelor
6 
STUDY ENDPOINTS
6.1 Efficacy endpoints 
Not applicable. 

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6.2 Pharmacokinetic and pharmacodynamic endpoints 
6.2.1 Pharmacodynamic endpoints 
The primary PD endpoint is the PD response that is defined for each subject as a 
PRU < 100 starting 30 min after injection and lasting for at least 3 h, as measured via the 
VerifyNow® assay. This corresponds to inhibition of ADP-induced platelet aggregation 
(IPA) > 80% [Gaglia 2011, Gremmel 2009, Varenhorst 2009]. 
6.2.2 Pharmacokinetic endpoints 
The plasma PK parameters of ACT-246475 will be derived by non-compartmental 
analysis of the plasma concentration-time profiles. PK endpoints include: 
•
Cmax.
•
tmax.
•
The AUC from time zero to 24 h time point (AUC0–24h).
6.3 Safety endpoints 
The safety endpoints will be assessed up to EOS: 
•
Treatment-emergent AEsb (TEAEs) and SAEs.
•
All AEs and SAEs.
•
Change in vital signs (systolic and diastolic arterial BP and pulse rate) from baseline
to all assessed time points during the study.
•
Treatment-emergent ECG abnormalities.
•
Change from baseline to each measured time point in ECG variables: heart rate, and
the intervals: PQ/PR, QRS, QT, RR, QT corrected with Bazett’s formula (QTcB), QT
corrected with Fridericia’s formula (QTcF).
•
Change from baseline to each measured time point for clinical laboratory tests.
•
Treatment-emergent marked laboratory abnormalities.
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits 
The study visits are listed in Table 2. For all visits, the subjects must be seen on the 
designated day. A follow-up safety visit must be performed 30–37 days after the single 
administration of study treatment. 
b A treatment-emergent AE is any AE temporally associated with the administration of study treatment (until 48 h after 
study treatment administration) whether or not considered by the investigator as related to study treatment. 

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7.1.1 Screening/re-screening 
Screening starts with the signature of the informed consent. The date on which the first 
screening assessment is performed corresponds to the date of the Screening visit. 
It is the responsibility of the investigator/delegate to obtain written informed consent 
from each subject participating in this study after adequate face-to-face explanation of the 
objectives, methods and potential hazards of the study. The subjects who agree to 
participate in the study and the investigator/delegate must sign the ICF prior to any 
study-related assessment or procedure. 
Subjects who have signed informed consent when the enrollment target has been met 
may still be randomized. 
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, insufficient washout period of a forbidden medication). 
All screening assessments must be repeated at the time of re-screening unless they were 
performed within 1 week (7 days) of re-screening. 
Screening (and re-screening) will be performed through the IRT system which will 
provide a unique subject number. 
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., AE), appropriate assessments will be performed 
based on the judgment of the investigator and the results will be recorded in the CRF. 
After an unscheduled visit, the regular scheduled study visits must continue according to 
the planned visit and assessment schedule. 

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Table 2 
Visit and assessment schedule 
PERIOD 
SCREENING PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
Visit 
Visit 1 
Visit 2 
(Randomizationc) 
Visit 3 
EOS Visit (Visit 4; 
Telephone call) 
Study Day 
Day −21 to Day −1 
Day 1 
Day 2 
Study treatment administration + 
30–37 days 
Informed consent 
X 
Eligibility 
X 
Xf 
Demographics and medical history 
X 
Physical examination 
X 
Xa 
X 
Body weight and height 
X 
Previous/concomitant therapy 
X 
X 
X 
X 
Urine pregnancy testg 
X 
X 
X 
Vital signs (BP, Pulse rate) 
X 
Xb 
Xb 
12-lead ECG
Xb 
Xb 
Laboratory testse
X 
Xa, f 
Xh 
PK blood sampling
Xb 
Xb 
VerifyNow®
X 
Xb, c 
Xb 
LTA (for patients ≥ 50.0 kg only) d
X 
Xb, c 
s.c. injection (ACT-246475 or placebo)
X 
AEs/SAEs
X 
X 
X 
X 
a.
Physical examination and laboratory tests do not need to be repeated if screening assessments were performed within 7 days of Visit 2 and are to be performed pre-
dose.
b.
Refer to Table 3 for detailed timing of assessments.
c.
Randomization will be performed after the pre-dose blood sampling for VerifyNow® and LTA assessments on Day 1. The dose allocated (8 mg or 16 mg) must not
be communicated to the subject.
d.
No blood samples are to be collected for LTA assays for subjects with body weight < 50.0 kg (110 lbs), only VerifyNow® assays are performed for these subjects.

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e.
Laboratory assessments include chemistry, hematology, and INR.
f.
If screening hemoglobin results are not available at time of randomization, it is acceptable to randomize a subject based on a local laboratory result if blood sample
was collected during the screening period.
g.
For women of childbearing potential only.
h.
If the 24 h post-dose central laboratory sample is lost or cannot be analyzed for whatever reason, the investigator may collect an additional sample for repeat
analysis, as deemed medically needed, unless a local laboratory sample was collected within the same time-window and these test results are available.
AE, Adverse event; BP, Blood pressure; ECG, Electrocardiogram; EOS, End-of-Study; INR, International normalized ratio; LTA, Light transmission aggregometry; 
PK, Pharmacokinetics; s.c., Subcutaneous; SAE, Serious adverse event. 
Table 3 
Time points of main study assessments 
PERIOD 
TREATMENT PERIOD 
Visit 
Visit 2 (Randomizationa) 
Visit 3 
Study Day 
Day 1b 
Day 2b 
Time point 
Pre-dose 
0 min 
15 min 
±1 min 
30 min 
±2 min 
1h 
±3 min 
2h 
±6 min 
4h 
±12 min 
8h 
±24 min 
24h 
±2h 
Vital signs (BP, Pulse rate) 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
Xd 
X 
PK Blood sampling
X 
X 
X 
X 
X 
X 
X 
X 
VerifyNow®
Xa 
X 
X 
X 
X 
X 
X 
X 
LTA (for patients ≥ 50.0 kg only)c
Xa 
X 
X 
X 
X 
s.c. injection (ACT-246475 or placebo)
X 
a.
Randomization will be performed after pre-dose blood sampling for VerifyNow® and LTA assessments on Day 1. The dose allocated (8 mg or 16 mg) must not be
communicated to the subject.
b.
The following order of assessments is to be followed (as applicable): PK sample (to be collected at the protocol-defined time point), VerifyNow® sample, LTA
sample.
c.
No blood samples are to be collected for LTA assays for subjects with body weight < 50.0 kg (110 lbs), only VerifyNow® assays are performed for these subjects.
d.
Time window for performing the post-dose ECG is ±30 min.
BP, Blood pressure; ECG, Electrocardiogram; EOS, End-of-Study; LTA, Light transmission aggregometry; PK, Pharmacokinetics; s.c., Subcutaneous.

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7.2 Study assessments 
The study assessments and their respective timing are listed in Table 2 and Table 3. 
All study assessments will be performed by qualified study personnel: medical, nursing, 
or specialist technical personnel, and will be recorded in the CRF, unless otherwise 
specified. Study assessments performed during unscheduled visits will also be recorded 
in the CRF. It is recommended to perform physical examination and measure vital signs 
(BP and pulse rate) prior to the blood samplings. 
At the PK/PD time points, the following order for blood sampling is to be applied: 
1. Hematology and chemistry samples (if any).
2. PK sample (to be collected at the protocol-defined time point according to the time
window defined in Table 3).
3. VerifyNow® sample.
4. LTA sample.
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available prior to screening of the 
first subject. Calibration certificates of other equipment must be available as per local 
requirements: 
•
Temperature measurement devices for study treatment storage area and freezer used
for PK samples storage.
•
VerifyNow® and LTA devices.
•
Centrifuges used for preparation of the platelets for LTA assay.
7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristic data to be collected on all subjects, including 
age, sex, race, and ethnicity. Relevant medical history / current medical conditions (e.g., 
chronic and ongoing acute conditions, serious past conditions) present before signing 
informed consent will be recorded on the medical history CRF form. Where possible, 
diagnoses and not symptoms will be recorded. 
Medical history of special interest will be captured on the specific Medical History CRF 
form and includes, when applicable, the date of the most recent event for: 
•
MI, stroke, and TIA.
•
PCI or coronary artery bypass graft.
•
Peripheral vascular surgery.

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For subjects who failed screening, at least the following data will be recorded in the CRF 
if available: 
•
Baseline demographics and physical characteristics (i.e., age, race/ethnicity, body
weight, height, sex).
•
LTA and VerifyNow® assessment results.
•
Central laboratory and central ECG results.
•
Reason for screening failure.
•
AEs and SAEs.
7.2.2 Efficacy assessments 
Not applicable. 
7.2.3 Pharmacokinetic and pharmacodynamic assessments 
7.2.3.1 Pharmacodynamic assessments 
7.2.3.1.1 Procedures for blood sampling 
The different time points for PD blood samples collection are detailed in Table 2 and 
Table 3. 
The blood samples for PD assessments are to be collected immediately after the blood 
samples for PK or laboratory assessments. If, for any reason, this is not possible, a 2 mL 
volume of blood needs to be discarded prior to collection of the PD blood samples. 
PD blood samples will be collected by direct venipuncture or via an i.v. catheter placed in 
an antecubital or large forearm vein in the arm, using 18–21 gauge needles. 
Blood will be drawn into 3-mL vacuum tubes: 2 samples for LTA assay and one sample 
for VerifyNow® assay. Collection tubes for both LTA and VerifyNow® assays will 
contain 
phenylalanine-proline-arginine-chloromethyl 
ketone 
(PPACK) 
as 
an 
anticoagulant. The centrifugation step should be performed within 1 h after sampling. 
The platelet aggregation assays must be performed preferably within 1 h of blood 
collection and not exceeding 2 h. The date and the exact actual clock time of collection of 
each blood sample (including the unscheduled ones, if any) will be entered in the CRF. 
Detailed handling instructions for PD samples (LTA and VerifyNow® samples) are 
provided in the laboratory manual. 
7.2.3.1.2 Bioanalysis 
ADP-induced platelet aggregation will be evaluated by 2 different assays, VerifyNow® 
and LTA, both measuring platelet-induced aggregation as an increase in light 
transmittance [Michelson 2009]. 

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All PD measurements will be performed at the site by trained staff using validated 
procedures. Detailed instructions for the analysis of the PD samples (LTA and 
VerifyNow®) are provided in the laboratory manual. 
7.2.3.1.2.1 VerifyNow® Assay 
The blood sample will be inserted into the calibrated VerifyNow® system. 
Platelet-induced aggregation is measured with ADP as the agonist. The assay will be run 
according to the manufacturer’s instructions. The VerifyNow® system will provide the 
results as PRU, corresponding to the extent of ADP-mediated aggregation measured in 
the ADP channel. 
The VerifyNow® system will be used with 2 different tests depending on local 
availability:  
•
The VerifyNow® P2Y12 test reports platelet aggregation as PRU. In addition, a
second channel with an internal standard consisting of thrombin receptor agonists is
used for calculation of the percent of platelet aggregation inhibition. The VerifyNow®
P2Y12 test is only available in Europe.
•
The VerifyNow® PRU test does not have an internal standard and only reports
platelet aggregation as PRU. It is globally available and will be used where the
VerifyNow® P2Y12 test is not available.
7.2.3.1.2.2 Light transmission platelet aggregometry 
The two 3 mL LTA blood samples will be centrifuged at 200 g for 7 min, the rotor should 
then come to a halt without brakes (brakes position 0 = switched off). This will allow for 
preparation of PRP. The assay will be performed with a light transmission aggregometer 
approved by the sponsor (e.g., Chrono-log 490, PAP-4, PAP-8, APACT), recording the 
aggregation after addition of 20 μM ADP as agonist for 6 min. The results are expressed 
as a percent change in light transmittance at maximum peak platelet aggregation and at 
final platelet aggregation after 6 min, calculated relative to the baseline signal of 0%. 
The measurements will be performed in duplicate. 
7.2.3.2 Pharmacokinetic assessments 
7.2.3.2.1 Procedures for blood sampling 
Blood will be collected by direct venipuncture or via an i.v. catheter placed in an 
antecubital vein in the arm in a 4 mL Monovette® or equivalent tubes containing 
ethylenediaminetetraacetic acid (EDTA).  
PK blood samples have to be processed within 30 min of collection. Instructions 
regarding sample collection, processing, labeling, and storage conditions are detailed in 
the laboratory manual. 

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The time points for PK assessment blood samples are described in Table 3. 
The date and exact actual clock time of collection of each blood sample will be entered in 
the CRF. 
7.2.3.2.2 Bioanalysis 
The analysis of ACT-246475 in plasma will be performed using a validated liquid 
chromatography coupled to tandem mass spectrometry assay. 
The foreseen lower limit of quantification is 1 ng/mL. Concentrations will be calculated 
by interpolation from a calibration curve. Quality control samples will be analyzed 
throughout the study. Their measured concentrations will be used to determine 
between-run and overall precision and accuracy of the analysis. 
7.2.4 Safety assessments 
The definitions, reporting, and follow-up of AEs, SAEs, and pregnancies are described in 
Section 9. 
7.2.4.1 Physical examination 
Physical examination will be performed according to site standard medical practice for 
subjects with stable CAD. 
Other exams will be performed if indicated, based on medical history and/or symptoms. 
Information for all physical examinations must be included in the source documentation 
at the study site. The observations will not be directly reported in the CRF. Clinically 
relevant findings that are present prior to signing of informed consent must be recorded 
on the Medical History CRF form. Physical examination findings made after signing of 
informed consent that meet the definition of an AE [Section 9.1.1] must be recorded on 
the AE form of the CRF. 
7.2.4.2 Vital signs 
Systolic and diastolic BP and pulse rate will be measured in subjects in supine or sitting 
position after at least 5 minutes of rest. It is recommended to use the same position and 
same arm for all measurements of the same subject. 
7.2.4.3 Weight and height 
Height and body weight will be measured in indoor clothing but without shoes. 
7.2.4.4 ECG assessment 
A standard 12-lead ECG will be performed with subject in the supine position, after a 
recommended 5-minute resting time. 

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Any clinically relevant ECG findings that are present prior to the administration of study 
treatment must be documented in the Medical History section of the CRF. 
Any clinically relevant ECG finding which is found after the study treatment 
administration and was not present at Screening or worsened during the study must be 
reported as an AE as appropriate [see Section 9.1.1]. 
A central ECG service (see ECG manual for contact details) will be used for ECG 
evaluation. 
Details about collection of ECG data, and the reporting of results and abnormalities, can 
be found in the ECG manual provided to the investigator. 
7.2.5 Laboratory assessments 
7.2.5.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits.  
Exceptional circumstances that may require recording of local laboratory results of the 
variables described in Section 7.2.5.2 (with corresponding normal ranges) include 
hospitalization of the subject due to a medical emergency, and missing central laboratory 
results from a scheduled or unscheduled visit. 
If the 24 h post-dose central laboratory sample is lost or cannot be analyzed for whatever 
reason, the investigator may collect an additional sample for repeat analysis, as deemed 
medically needed, unless a local laboratory sample was collected within the same 
time-window and these test results are available. 
Central laboratory reports will be sent to the investigator. In the event of specific 
(predefined) laboratory abnormalities, the central laboratory will alert sponsor personnel 
and the concerned site personnel. Alert flags that will trigger such notifications are 
displayed in the laboratory manual. 
All laboratory reports must be reviewed, signed and dated by the investigator or delegate 
within 10 working days of receipt and filed with the source documentation. 
The investigator/delegate must indicate on the laboratory report whether abnormal values 
are considered clinically relevant or not. Clinically relevant laboratory findings that are 
known at the time of signing of informed consent must be recorded on the Medical 
History form of the CRF. Any clinically relevant laboratory abnormalities detected after 
signing of informed consent must be reported as an AE or SAE as appropriate [see 
Section 9], and must be followed until the value returns to within the normal range or is 
stable, or until the change is no longer clinically relevant. 

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Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.2.5.2 Laboratory tests 
7.2.5.2.1 Hematology 
•
Hemoglobin (g/L)
•
Hematocrit (L/L)
•
Erythrocyte count (109/L)
•
Leukocyte count with differential counts (109/L)
•
Platelet count (109/L)
7.2.5.2.2 Clinical chemistry
•
Alanine aminotransferase (U/L)
•
Aspartate aminotransferase (U/L)
•
Alkaline phosphatase (U/L)
•
Total and direct bilirubin (μmol/L)
•
Creatinine (μmol/L)
•
Creatinine clearance (eGFR) estimated with Cockcroft-Gault formula
•
Blood urea nitrogen (mmol/L)
•
Uric acid (μmol/L)
•
Total cholesterol (mmol/L)
•
Sodium, potassium, chloride, calcium (mmol/L)
•
Albumin (g/L)
7.2.5.2.3 Coagulation tests
•
International normalized ratio
7.2.5.2.4 Pregnancy test
•
Urine pregnancy tests

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8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion 
A subject who has received study treatment and completed the follow-up period is 
considered to have completed the study. 
8.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw from 
further participation in all components of the study (i.e., withdrawal of consent), if they 
die, or are lost to follow-up. If a subject withdraws consent, no further data will be 
collected in the CRF from the date of withdrawal onward. The investigator may withdraw 
a subject from the study (without regard to the subject’s consent) if, on balance, he/she 
believes that continued participation in the study would be contrary to the best interests of 
the subject. Withdrawal from the study may also result from a decision by the sponsor for 
any reason, including premature termination or suspension of the study. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual failed. The site must take preventive measures to 
avoid a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted if the subject 
cannot be reached). If the subject cannot be reached, the site must make a reasonable 
effort to contact the subject, document all attempts, and enter the loss of follow-up 
information into the CRF. The following methods must be used: at least 3 telephone calls 
must be placed to the last available telephone number and one registered letter must be 
sent by post to the last available home address. Additional methods may be acceptable if 
they are compliant with local rules/regulations (e.g., a visit by site personnel to the 
subject’s home), respecting the subject’s right to privacy. If the subject is still 
unreachable after all contact attempts listed above, he/she will be considered to be lost to 
follow-up. 
If premature withdrawal occurs for any reason, the reason (if known) for premature 
withdrawal from the study, along with who made the decision (subject, investigator, or 
sponsor personnel), must be recorded in the CRF, if known. 
If, for whatever reason (except death or loss-to-follow-up), a subject is withdrawn from 
the study, the investigator should make efforts to schedule a last appointment / telephone 
call to assess the safety and wellbeing of the subject. Data obtained during this last 
appointment / telephone call will be recorded in the subject’s medical records but it will 
not be collected in the CRF. The investigator must provide follow-up medical care for all 

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subjects who are prematurely withdrawn from the study, or must refer them for 
appropriate ongoing care, as described in Section 8.4. 
8.3 Premature termination or suspension of the study 
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 a study is prematurely suspended or terminated, the sponsor/delegate will promptly 
inform the investigators, the IECs/IRBs, and HAs, as appropriate, and provide the reasons 
for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator — in 
agreement with the sponsor — must promptly inform all enrolled subjects and ensure 
their appropriate treatment and follow-up, as described in Section 8.4. The 
sponsor/delegate may inform the investigator of additional procedures to be followed in 
order to ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
In addition, if the investigator suspends or terminates a study without prior agreement 
from the sponsor, the investigator must promptly inform sponsor personnel and the 
IEC/IRB, and provide both with a detailed written explanation of the termination or 
suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of a study, the 
investigator must promptly notify sponsor personnel and provide a detailed written 
explanation of the termination or suspension. 
8.4 Medical care of subjects after study completion / withdrawal from study 
The subject’s standard of care will not be affected by study participation. For this PK/PD 
and safety study, subjects will receive 1 single administration of study treatment on top of 
their standard of care. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
9.1.1 Definition of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A TEAE is any AE temporally associated with the use of study treatment until 48 h after 
study treatment administration whether or not considered by the investigator as related to 

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study treatment. The 48-h window for TEAEs has been defined to include at least 
5 half-lives of ACT-246475. 
AEs include: 
•
Exacerbation of a pre-existing disease.
•
Increase in frequency or intensity of a pre-existing episodic disease or medical
condition.
•
Disease or medical condition detected or diagnosed during the course of the study
even though it may have been present prior to the start of the study.
•
Continuous persistent disease or symptoms present at study start that worsen
following the signing of informed consent.
•
Abnormal assessments, e.g., change on physical examination, ECG findings, if they
represent a clinically significant finding that was not present at study start or
worsened during the course of the study.
•
Laboratory test abnormalities if they represent a clinically significant finding,
symptomatic or not, which was not present at study start or worsened during the
course of the study.
Overdose, misuse, abuse of the study treatment and study treatment errors will be 
reported as an AE. 
9.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a 3-point scale (mild, moderate, severe) and is 
reported on specific AE pages of the CRF. 
All changes in intensity of an AE during the study will be reported in the CRF. 
The three categories of intensity are defined as follows: 

Mild
The event may be noticeable to the subject. It does not usually influence daily activities,
and normally does not require intervention.

Moderate
The event may make the subject uncomfortable. Performance of daily activities may be
influenced, and intervention may be needed.

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
Severe
The event may cause noticeable discomfort, and usually interferes with daily activities.
The subject may not be able to continue in the study, and treatment or intervention is
usually needed.
A mild, moderate, or severe AE may or may not be serious [see Section 9.2.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
used on a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations. 
9.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by the investigator. 
9.1.4 Reporting of adverse events 
All AEs with an onset date after signing of informed consent and up to 30 days after 
study treatment administration must be recorded on specific AE pages of the CRF. 
9.1.5 Follow-up of adverse events 
AEs still ongoing more than 30 days after study treatment administration must be 
followed up until they are no longer considered clinically relevant or until stabilization. 
The follow-up information obtained after the subject’s EOS telephone call will not be 
collected by the sponsor. 
9.2 Serious adverse events 
9.2.1 Definitions of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the 
following criteria: 
•
Fatal.
•
Life-threatening: Refers to an event in which the subject was at risk of death at the
time of the event. It does not refer to an event that hypothetically might have caused
death had it been more severe.
•
Requiring in-patient hospitalization or prolongation of existing hospitalization.
•
Resulting in persistent or significant disability or incapacity.
•
Congenital anomaly or birth defect.

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•
Medically significant: Refers to important medical events that may not immediately
result in death, be life-threatening, or require hospitalization but may be considered to
be SAEs when, based upon appropriate medical judgment, they may jeopardize the
subject, and may require medical or surgical intervention to prevent one of the
outcomes listed in the definitions above.
The following reasons for hospitalization are not considered as SAEs: 
•
Hospitalization for cosmetic elective surgery, or social and/or convenience reasons
(including hospitalization related to protocol procedures).
•
Hospitalization for pre-planned (i.e., planned prior to signing informed consent)
surgery or standard monitoring of a pre-existing disease or medical condition that did
not worsen, e.g., hospitalization for coronary angiography in a subject with stable
angina pectoris.
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
9.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent up to 30 days after study treatment 
administration must be reported on AE pages in the CRF and on a SAE form, regardless 
of the investigator-attributed causal relationship with study treatment or study-mandated 
procedures. 
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures (e.g., discontinuation of a subject’s previous treatment 
during a washout period leading to exacerbation of underlying disease). 
All SAEs must be reported by the investigator to the sponsor’s Global Drug Safety 
department within 24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on a SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be 
related to study treatment. 
The SAE forms must be sent to the sponsor’s Global Drug Safety department (contact 
details are provided on the SAE form). The investigator must complete the SAE form in 
English, and must assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form.  

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Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The sponsor’s Global Drug Safety personnel may contact the 
investigator to obtain further information. 
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The expectedness of an adverse reaction is determined by the sponsor in the reference 
safety information (RSI) section provided in the most recent version of the IB. Any SAE 
that is assessed as related and unexpected against the RSI is known as a SUSAR and must 
be reported by the sponsor/delegate to concerned HAs (including the EudraVigilance 
database if the study is conducted in Europe), IECs/IRBs and investigators. 
9.2.3 Follow-up of serious adverse events 
SAEs still ongoing more than 30 days after study treatment administration must be 
followed up until resolution or stabilization, or until the event outcome is provided. 
The follow-up information obtained after the subject’s EOS telephone call must be 
reported to the sponsor’s Global Drug Safety department, but it is not recorded in the 
CRF. 
9.2.4 After the 30-day follow-up period 
New SAEs occurring after the 30-day follow-up period must be reported to the sponsor’s 
Global Drug Safety department within 24 hours of the investigator’s knowledge of the 
event, only if considered by the investigator to be causally related to previous exposure to 
the study treatment. 
9.3 Pregnancy 
If a woman becomes pregnant during study participation, the investigator must counsel 
the subject and discuss the risks of continuing with the pregnancy and the possible effects 
on the fetus. 
9.3.1 Reporting of pregnancy 
Any pregnancy occurring after study start (i.e., signing of informed consent) up to 
30 days following study treatment administration must be reported within 24 hours of the 
investigator’s knowledge of the event. 
Pregnancies must be reported on the Pregnancy form, which is faxed to the sponsor’s 
Global Drug Safety department (see contact details provided on the Pregnancy form), and 
on an AE page in the CRF. 

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9.3.2 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 occurring during the follow-up period after study 
treatment administration must be reported on separate AE pages in the CRF. Any SAE 
occurring during the pregnancy must be reported on an SAE form as described in 
Section 9.3.1. 
9.4 Study safety monitoring 
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific examinations as required) is monitored and reviewed on a continuous basis 
by the sponsor’s clinical team (in charge of ensuring subjects’ safety as well as data 
quality). In addition, a Safety Event Committee is monitoring safety data 
[see Section 3.4]. 
10 STATISTICAL METHODS 
All statistical analyses will be conducted by the sponsor or by designated CROs 
supervised by the sponsor. 
A statistical analysis plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. 
Any deviation(s) from the original statistical plan described hereafter will be described 
and justified in the SAP or in the CSR, as appropriate. 
10.1 Analysis sets 
10.1.1 Screened analysis set 
The Screened analysis set includes all subjects who are screened and have a subject 
identification number. 
10.1.2 Randomized analysis set 
The Randomized analysis set includes all subjects who have been assigned to a 
double-blind study treatment. 
10.1.3 Full analysis set 
The Full analysis set (FAS) includes all randomized subjects who have been administered 
the study treatment.  

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In order to adhere to the intention-to-treat principle as much as possible: 
•
Subjects are evaluated according to the study treatment they have been assigned to
(which may be different from the study treatment they have received),
•
All available data are included.
10.1.4 Per-protocol analysis set 
The Per-protocol set (PPS) comprises all subjects from the FAS who complied with the 
protocol sufficiently to allow adequate estimation of the treatment effects. Criteria for 
sufficient compliance include exposure to treatment, availability of key endpoints 
measurements and absence of major protocol deviations that have an impact on the 
treatment effect. 
The full list of criteria will be detailed in the SAP before making the full randomization 
information available. 
10.1.5 Safety set 
The Safety set (SS) includes all subjects who received study treatment. Subjects will be 
evaluated according to the actual treatment they received, which may differ from the 
randomly assigned treatment. 
10.1.6 Pharmacokinetic analysis set 
The PK analysis set includes all subjects in the SS who have at least one PK sample 
collected after administration of study treatment. 
10.1.7 Usage of the analysis sets 
The PD analysis will be performed on the FAS based on the study treatment as 
randomized. Sensitivity analyses will be conducted using same endpoints as specified in 
Section 10.3 on the PPS. 
Safety analyses will be performed on the SS based on actual study treatment received. 
Subject listings will be based on the SS, unless otherwise specified. Subject disposition 
will be described for the Screened analysis set. 
Table 4 describes the analysis sets used for the analysis of each data set. 

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Table 4 
Analysis datasets 
Analysis 
Screened 
set 
RND 
FAS 
PPS 
SS 
PK set 
Subject disposition 
X 
Baseline and disease characteristics 
(x)
X
(x) 
Previous and concomitant medication 
X
Study treatment exposure 
X
(x) 
PD endpoints analyses 
X
(x) 
Safety and tolerability analyses 
X 
PK data analysis 
X 
Note: Selected safety parameters, X: main analysis, (x): Sensitivity analysis to be conducted only if > 10% difference 
of set size with set used for main analysis. 
FAS, Full analysis set; PD, Pharmacodynamic; PK, Pharmacokinetic; PPS, Per-protocol set; RND, Randomized set; 
SS, Safety set. 
10.2 Variables 
The absolute change from baseline to time T is defined as the algebraic difference 
between the value observed at time T minus the value at baseline. 
The relative change from baseline to time T is defined as the ratio of the absolute change 
from baseline to time T on the baseline value. 
Unless specified otherwise, the baseline value is defined as the arithmetic mean of the 
last 2 values collected during the screening phase prior to randomization. 
10.2.1 Primary efficacy variable(s) 
Not applicable. 
10.2.2 Key secondary efficacy variables 
Not applicable. 
10.2.3 Safety variables 
10.2.3.1 Adverse events 
An AE is defined as any event that is recorded on the AE CRF module regardless of the 
onset date. 
TEAEs are those AEs with onset date/time ≥ date/time of first study treatment 
administration and ≤ 48 h after date/time of last study treatment administration. 
The handling of missing or incomplete date/time of AEs and assessments will be 
described in the SAP. 

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10.2.3.2 Laboratory data 
Laboratory analyses are based on data received from the central laboratory 
[see Section 7.2.5.2]. All transferred central laboratory data are taken into account 
regardless of whether they correspond to scheduled or unscheduled assessments. 
Baseline laboratory test refers to the latest laboratory test performed prior to the first 
study treatment administration.  
End-of-treatment laboratory test refers to the laboratory test performed on the day 
following the day of study treatment administration (Visit 3). 
For each continuous laboratory parameter, the following variables will be summarized: 
•
Absolute value at each time point,
•
Absolute change from baseline to each time point,
•
Treatment-emergent marked laboratory abnormalities (i.e., up to 48 h after study
treatment administration).
For categorical laboratory parameters, the following variables will be summarized: 
•
Proportion of subjects by categories at each time point.
Unless stated otherwise, no imputation for missing laboratory values will be performed.
10.2.3.3 ECG 
ECG recording is performed at the time points described in Table 3. 
•
Treatment-emergent ECG abnormalities (i.e., up to 48 h after study treatment
administration).
•
Absolute change from baseline to each time point in ECG variables: HR, and the
intervals: PQ/PR, QRS, QT, RR, QTcB, and QTcF.
10.2.3.4 Vital signs 
•
Absolute value in vital signs at each assessed time point during the study.
•
Relative change from baseline to each measured time point in vital signs (systolic and
diastolic arterial BP and pulse rate).
10.2.4 Pharmacokinetic and pharmacodynamic variables 
10.2.4.1 Pharmacokinetic variables 
Plasma concentrations per time point will be listed by treatment arm and subject, and 
summarized by time point and dose group using arithmetic and geometric mean, 

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minimum, median, maximum, standard deviation (SD), standard error (SE), and 2-sided 
95% confidence interval (CI) of the means and coefficient of variation (CV) in %. 
PK parameters will be derived using non-compartmental methods: 
•
Cmax, tmax, and AUC0–24h will be listed by dose group and subject and will be
summarized by dose group.
•
Cmax, tmax*, and AUC0–24h will be summarized with arithmetic mean, geometric mean,
minimum, median, maximum, SD, SE, CV (%), and 95% CI of the arithmetic and
geometric means.
(* For tmax the geometric mean and its 95% CI will not be calculated).
•
Log-transformed Cmax and AUC0–24h values will be summarized with mean and SD of
the logs.
10.2.4.2 Pharmacodynamic variables 
The primary PD variable is the IPA as measured by VerifyNow® at each time point, as 
described in table of assessments [Table 2 and Table 3]. 
The primary PD endpoint is the PD response that is defined for each subject as a 
PRU < 100 starting 30 min after injection and lasting for at least 3 h, as measured via 
VerifyNow®. 
Additional PD variables related to the main ones will also be considered at each time 
point: 
•
Extent of aggregation (measured through LTA).
•
Absolute PRU values (for VerifyNow®).
•
% of subjects at 8 h after study treatment injection with PRU value < 100 or
> 1.05 × baseline value.
10.3 Description of statistical analyses 
All analyses will be conducted by treatment arm on the FAS, i.e., ACT-246475 8 mg, 
ACT-246475 16 mg, and placebo. 
10.3.1 Overall testing strategy 
The study is intended to assess the effect of ACT-246475 on platelet aggregation. 
The primary null hypotheses will be tested at a 0.025 alpha level for each comparison to 
placebo, and then, if the null hypothesis is rejected for at least 1 of the 2 active arms, it 
will be completed by testing in each active arm that the proportion of patients achieving a 
response is statistically greater than 70%.  

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The study will be declared to be positive with regard to the primary objective if, for at 
least 1 of the 2 active arms, the 2 null hypotheses are sequentially rejected at an adjusted 
alpha level of 0.025. 
No imputation will be considered for handling missing values in the main analysis of PD. 
Imputations may be performed in sensitivity/exploratory analyses, if deemed necessary, 
e.g., if more than 10% missing values at a given time point.
10.3.2 Analysis of the primary pharmacodynamic variable 
The study is designed to demonstrate that ACT-246475 treatment enables a large 
proportion (a target of 85%) of the enrolled subjects to achieve a clinically meaningful 
level of IPA, i.e., PRU < 100. 
10.3.2.1 Hypotheses and statistical model 
The primary goal is to determine that the proportion p of subjects receiving a dose of 
ACT-246475, who achieve the PD response as measured by VerifyNow®, is statistically 
greater than 70%. 
In order to achieve this objective, the testing strategy will consider a sequential 
approach demonstrate a statistically significant difference between the control arm 
(placebo) and at least 1 of the active arms, then to confirm that the observed response rate 
(Pr) in the same active arm is statistically significantly greater than the predefined 
response rate. 
The comparison of each of the 2 active treatment arms will be conducted vs placebo, with 
the following hypotheses:  
Hp0HD: pplacebo = pHD 
vs 
Hp1HD: pplacebo ≠ pHD 
AND 
Hp0LD: pplacebo = pLD 
vs 
Hp1LD: pplacebo ≠ pLD
Where, pplacebo is the proportion of responders in Placebo arm, pHD is the proportion of 
responders in the ACT-246475 16 mg arm, and pLD is the proportion of responders in the 
ACT-246475 8 mg arm. 

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The 2 null hypotheses will be tested for each dose by a 2-sided z-test at an overall 
significance level (alpha) of 0.05 adjusted for multiplicity using the Bonferroni method, 
i.e., 0.025 for each comparison.
Assuming that either Hp0HD, or Hp0LD, or both are rejected, then the following hypotheses 
will be tested for each of the active doses that were statistically significantly different 
from placebo:  
H0: Presponders = 0.70  
vs  
H1: Presponders > 0.70 
The null hypothesis will be tested for each dose by a 1-sided z-test at an overall 
significance level (alpha) of 0.05 adjusted for multiplicity using the Bonferroni method, 
i.e., 0.025 for each comparison.
10.3.2.2 Handling of missing data 
Subjects for whom determination of the response is not possible will be counted as 
non-responders in the main analysis; no other imputation will be considered. 
10.3.2.3 Main analysis 
The primary statistical analysis will be performed on the FAS population for each dose 
level. 
The first set of null hypotheses (Hp0HD and Hp0LD) will be tested for each dose by a 
2-sided z-test at an overall significance level (alpha) of 0.05 adjusted for multiplicity
using the Bonferroni method, i.e., 0.025 for each comparison.
The second null hypothesis (H0) will be tested for each dose by a 1-sided z-test. The 
estimated proportion of responders in each arm and the corresponding 95% CI will be 
provided.  
A longitudinal analysis of the treatment effect, from start of treatment up to 8 h after 
injection, on platelet reactivity as measured by VerifyNow®, i.e., PRU value, will be 
performed using a mixed model with PRU as the dependent variable, subject as a random 
factor, and treatment (8 mg, 16 mg, and placebo), injection site (abdomen, thigh), PRU 
level at randomization (stratification levels), age (continuous), gender (male, female), and 
assessment time (continuous) as fixed factors. The model will also include (treatment × 
injection site) as an interaction term to assess consistency of treatment effect across 
injection sites. 
A logistic regression analysis of the PD response will be performed using the same factor 
as covariates. 

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Summary of PD response, in terms of number (%) of subjects, will be provided. IPA as 
measured by VerifyNow® will also be summarized as a continuous parameter. 
10.3.2.4 Supportive/sensitivity analyses 
The consistency across the following subgroups will be assessed by repeating the primary 
endpoint analysis, assuming there are a sufficient number of subjects: 
1. Age: < 55 vs ≥ 55 years
2. Body mass index: < 25.0 vs (≥ 25.0 and < 30.0) vs ≥ 30.0 kg/m2
3. Sex: male vs female
4. Diabetes mellitus at baseline: yes vs no
5. Chronic kidney disease: yes vs no
An additional analysis of the supportive PD endpoint (LTA-PD response) will be 
conducted using the same approach as described for the primary PD analysis. 
Further analyses will be described in the SAP as necessary. 
10.3.3 Analysis of key secondary efficacy variable(s) 
Not applicable. 
10.3.4 Analysis of the safety variables 
Unless noted otherwise, the SS will be used for summaries and listings of safety data. 
10.3.4.1 Adverse events 
AEs coded using the most recent version of MedDRA, will be summarized (frequency 
counts and percentages) by system organ class and/or preferred term, and maximum 
intensity. 
Summaries will be provided for the following data: 
•
TEAEs.
•
TEAEs related to study treatment.
•
Treatment-emergent non-serious AEs.
•
Treatment-emergent SAEs.
•
Treatment-emergent SAEs related to study treatment.
•
TEAEs with fatal outcome.
•
TEAEs related to study treatment with fatal outcome.

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10.3.4.2 Laboratory data 
Unless noted otherwise, summaries and listings will include unscheduled assessments 
reported by the central laboratory. 
Descriptive summary statistics by scheduled visit will be provided for observed values 
and absolute changes from baseline in both hematology and blood chemistry laboratory 
variables. 
The absolute change from baseline to each time point for hematology and blood 
chemistry variables will be summarized. 
Number (%) of subjects with treatment-emergent marked laboratory abnormalities will be 
tabulated and all marked laboratory abnormalities will be listed. 
10.3.4.3 Vital signs, weight and physical examination 
Each summary and listing will include unscheduled assessments. 
Absolute changes from baseline to last value on study treatment in vital signs will be 
summarized. The absolute values at each time point will also be summarized. 
Physical examination abnormalities will be listed. 
10.3.4.4 Electrocardiograms 
Each ECG summary and listing will include unscheduled assessments. 
The absolute change from baseline to each time point for ECG variables will be 
summarized. The absolute values at each time point will be summarized. 
Number (%) of subjects having a marked ECG abnormality during the treatment period 
will be summarized. 
All ECG values for subjects with at least one marked ECG abnormality will be listed. 
10.4 Interim analyses 
No interim analysis planned. 
10.5 Sample size 
The sample size is based on the primary PD endpoint, which is the proportion of subjects 
achieving a predefined PD response as measured by VerifyNow®. The computation of the 
sample size was performed using the East 6.0 software (version 6.4.0.1, 30 Aug. 2016) 
from Cytel. 
This study includes 3 treatment arms, 2 active arms (ACT-246475 8 mg and 16 mg) and a 
placebo arm comprising the 2 dose-matching placebo groups. 

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The primary objective is to assess the effectiveness of ACT-246475 to allow subjects to 
achieve a predefined PD response, therefore the sample size will be provided in order to 
reach the necessary power to sequentially demonstrate that at least 1 of the 2 doses has a 
higher response rate than placebo and that this response rate is statistically significantly 
greater than the proportion of responders under H0. 
The sample size required for demonstrating a difference to placebo is based on an overall 
alpha of 0.05 (2-sided), adjusted for multiplicity using a Bonferroni method to 0.025 for 
each comparison, and a power of 0.9; the assumptions related to response rate under the 
null and alternative hypotheses are reported in the table below: 
Proportion of 
responders under H0 
(placebo) 
Proportion of 
responders under H1 
(active) 
Number of subjects 
(total) 
Number of 
subjects 
(per arm) 
50% 
75% 
(odds ratio of 3) 
288 
96 
The sample size required to demonstrate that the achieved response rate is different from 
70% is based on a 2-sided type I error (alpha) of 0.025, and a power of 0.9; the 
assumptions related to response rate under the null and alternative hypotheses, are 
reported in the table below: 
Proportion of 
responders under H0 
Proportion of 
responders under H1 
Number of subjects 
(total for the 2 active 
arms) 
Number of 
subjects 
(per arm) 
70% 
85% 
196 
98 
Therefore the study should include at least 98 subjects evaluable for the primary PD 
endpoint in each treatment arm. Assuming a rate of drop-out or non-evaluable data of 
about 10%, each arm will include 108 subjects leading to a total for the study of 
324 subjects. 
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for maintaining adequate and accurate source 
documents and trial records that include all pertinent observations on each of the site’s 
trial subjects. 

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Data reported in the CRF derived from source documents must be consistent with the 
source documents. 
CRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool). The investigator and site personnel will be 
trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification — an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to US 
21 CFR Part 11). 
Subject screening and randomization data will be completed for all subjects (i.e., eligible 
and non-eligible) through the IRT system and CRF. 
For each subject screened (i.e., who signed an ICF), regardless of study treatment 
administration, a CRF must be completed and signed by the investigator/delegate. This 
also applies to those subjects who fail to complete the study. If a subject withdraws from 
the study, the reason must be noted on the CRF. 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
the sponsor and any CROs, subjects must be identified only by number and never by their 
name or initials, date of birth, hospital numbers, or any other identifier. The 
investigator/delegate must keep a subject identification code list at the site, showing the 
screening/randomization number, the subject’s name, date of birth, and address or any 
other locally accepted identifiers. Documents identifying the subjects (e.g., signed ICF) 
must not be sent to the sponsor, and must be kept in strict confidence by the 
investigator/delegate. 
11.3 Database management and quality control 
CRFs will be used for all subjects. The investigators will have access to the site CRF data 
until the database is closed. Thereafter, they will have read-only access. The CRF must 
be kept current to reflect subject status at any time point during the course of the study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by 
sponsor/delegate personnel on an ongoing basis to look for unexpected patterns in data 
and for study monitoring. If discrepant data are detected, a query specifying the problem 
and requesting clarification will be issued and visible to the investigator/delegate via the 
CRF. 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 

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directly in the CRF, or simply a data correction in the CRF. 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 HA queries, it is also necessary to have access 
to the complete study records, provided that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples and ECGs will be processed through a central vendor and the results 
will be electronically sent to the sponsor. 
AEs are coded according to the latest MedDRA used by the sponsor. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate sponsor QS docs. After database closure, the investigator will receive the 
CRFs of the subjects of his/her site (including all data changes made) on electronic media 
or as a paper copy. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
Sponsor/delegate personnel and the investigators will ensure that the study is conducted 
in full compliance with this protocol, ICH-GCP Guidelines, the principles of the 
‘Declaration of Helsinki’, and with the laws and regulations of the country in which the 
study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed, and the date of 
approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  

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If a member of the study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
12.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according 
to ICH-GCP and Declaration of Helsinki guidelines and local regulations from each 
individual participating in this study and/or legally designated representative. The 
investigator/delegate must explain to subjects that they are completely free to refuse to 
enter the study, or to voluntarily withdraw from the study at any time for any reason 
without having to provide any justification. Special attention shall be paid to the 
information needs of specific subject populations and of individual subjects, as well as to 
the methods used to give the information. Adequate time shall be given for the subject 
and/or legally designated representative to consider his or her decision to participate in 
the study and it shall be verified that the subject has understood the information (e.g., by 
asking the subject to explain what is going to happen). 
The ICF will be provided in the country local language(s). 
Site personnel authorized to participate in the consent process and/or to obtain consent 
from the subject and/or legally designated representative will be listed on the Delegation 
of Authority form supplied by the sponsor/delegate. A study physician must always be 
involved in the consent process. 
The subject and/or legally designated representative and authorized site personnel listed 
on the Delegation of Authority form supplied by the sponsor/delegate must sign, 
personally date, and time (if the first study-mandated procedure is to be performed on the 
same day informed consent is obtained) the ICF before any study-related procedures 
(i.e., any procedures required by the protocol) begin.  
A copy (or a second original) of the signed and dated ICF is given to the subject and/or 
legally designated representative; the original is filed in the site documentation. The 
informed consent process must be fully documented in the subject’s medical records. 
This must include, at a minimum, the study reference, the subject number, the date and 
the information that a copy of the signed ICF was given to the subject/legally designated 
representative. Where applicable, this must also include the time and date when the 
subject was first introduced to the study, the time of consent, who participated in the 
consent discussion, who consented the subject and any additional person present during 
the consent process (e.g., the subject’s family member[s]) 
If the site intends to recruit subjects who are considered vulnerable (e.g., subject cannot 
read or write, or does not speak or understand the ICF language), additional measures 
must be implemented in order to ensure subject’s rights are respected and the consent 

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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 subjects are recruited. 
12.4 Compensation to subjects 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. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
There is no direct health benefit for the subjects participating in the study. Accordingly, 
subjects may receive financial compensation for the time spent in the clinical trial in 
compliance with local regulation. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB and/or the 
regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform the sponsor or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to the 
sponsor or (overruling) local requirements. 
All protocol deviations will be reported in the CSR. IECs/IRBs will be provided with 
listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, in 
accordance with local regulations and procedures.  
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the 
reconstruction and evaluation of the study. A number of attributes are considered of 
universal importance to source data and the records that hold those data. These include 
that the source data and records are attributable, legible, contemporaneous, original 

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(or certified copy), accurate, and complete. Changes to source data and records must be 
traceable, must not obscure the original entry and must be explained if necessary 
(e.g., via an audit trail).  
These records are to be classified into 2 different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
the sponsor’s requirements (i.e., as specified in the clinical study agreement), and 
national and/or international regulations, whichever would be the longest period. If the 
investigator cannot guarantee this archiving requirement at the site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and the sponsor to store these documents outside the site, so that 
they can be retrieved in case of a regulatory inspection. No study document should be 
destroyed without prior written approval from the sponsor. Should the investigator wish 
to assign the study records to another party, or move them to another location, the 
sponsor must be notified in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR 
Part 11 or equivalent standard) and if the CRA has been provided personal and restricted 
access to study subjects only, to verify consistency between electronic source data and 
the CRF during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the CRA. The printouts must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies containing the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s CRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per the sponsor’s instructions. If it were not possible for 
the CRA to observe this process, it would not be possible to rely on the site’s certified 
copies and therefore the site cannot be selected for the clinical study. 

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12.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required 
essential study documents are approved by the sponsor or delegate. The study treatment 
will be shipped to the site upon approval of the required essential documents. 
The principal investigator (PI) must ensure that all site personnel involved in the study 
are present during the SIV and will dedicate enough time to it. 
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter 
will be provided to the PI and filed in the ISF. 
During the study, the CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered in the CRFs and other protocol-related documents. Sponsor monitoring 
standards require full verification that informed consent has been provided, verification 
of adherence to the inclusion/exclusion criteria, documentation of SAEs, and the 
recording of the main PD, safety, and tolerability endpoints. Additional checks of the 
consistency of the source data with the CRFs will be performed according to the 
study-specific monitoring guidelines. The frequency of the monitoring visits will be 
based on subject recruitment rate and critical data-collection times. 
The PI must ensure that the CRF is completed after a subject’s visit (site visit or 
telephone call), and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review 
by the CRA. The required site personnel must be available during monitoring visits and 
allow adequate time to meet with the CRA to discuss study-related issues. 
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in 
a hospital other than the study site, the investigator is responsible for contacting that 
hospital in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. If a site does not enroll any 
subjects, the close-out visit may be performed prior to study database closure at the 
discretion of the sponsor. 

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12.9 Investigator Site File 
Each site will be provided with an ISF at the latest during the SIV. It will contain all the 
essential documents that are required to be up-to-date and filed at site as per ICH-GCP 
section 8. 
The ISF will include a table of contents listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is 
filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from the sponsor. If the site needs to 
transfer the ISF to another location and/or if site facility can no longer store the ISF, the 
PI must immediately inform the sponsor. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 
12.10 Audit 
The sponsor’s QA 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’s requirements (e.g., standard operating procedures) will also be verified. Prior to 
initiating this audit, the investigator will be contacted by the sponsor/delegate to arrange a 
time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 
12.11 Inspections 
HAs and/or IECs/IRBs may also conduct an inspection of this study (during the study or 
after its completion) at the site. 
Should an inspection be announced by a HA and/or IEC/IRB, the investigator must 
immediately inform the sponsor (usually via the CRA) that such a request has been made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 

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12.12 Reporting of study results and publication 
The sponsor/delegate will post the key elements of this protocol and the summary of 
results 
within 
the 
required 
timelines 
on 
publically 
accessible 
databases 
(e.g., clinicaltrials.gov, EU database), as required by law and regulation. 
Study results will be documented in a CSR that will be signed by sponsor representatives 
and the Coordinating Investigator. 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before submission to a peer-reviewed journal. 
The Coordinating Investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the 
study results with 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 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. 
The sponsor’s Policy on Scientific Publications can be found at: 
https://www.idorsia.com/documents/com/policies-charters/policy-scientific-
publications.pdf 

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