Clinical trial NCT03688555
Conditions: Bilateral Nasal Polyposis
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2018-10-19; Completion date: 2020-12-01
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the effect of ACT-774312 on the nasal polyps and will assess the safety and tolerability of ACT-774312 in the patients with bilateral nasal polyposis

Detailed description:
The clinical trial has 3 periods:

Screening and run-in period (4 Weeks). This period starts with the screening visit, and ends on Day 1, just before the first study treatment administration. At Visit 1, all participants will enter a run-in period of 4 weeks on mometasone furoate nasal spray of 2 actuations (50 μg per actuation) in each nostril twice daily (total daily dose of 400 μg), unless they were intolerant to twice daily intranasal corticosteroids, in which case they could use a lower dose regimen, i.e., 200 μg once daily.

Treatment period (ACT-774312 or placebo for 12 weeks). This period will start on Day 1 with the first administration of study treatment and consists of 4 visits: Week 2, Week 4, Week 8, and Week 12. Provided that the nasal polyp score (NPS) does not change during the run-in period, participants will be randomized to ACT-774312 (400 mg twice daily) or placebo (twice daily) for 12 weeks. During the double-blind randomized treatment all participants will continue with mometasone furoate nasal spray background therapy.

Post-treatment period (4 Weeks). This period will start after the Week 12 Visit and end at Week 16 (End-of-Study).

Arms: arm 1: Participants will receive ACT-774312 (400 mg twice daily) in the morning and evening with or without food for 12 weeks together with mometasone furoate nasal spray. arm 2: Participants will receive placebo twice daily in the morning and evening with or without food for 12 weeks together with mometasone furoate nasal spray.
Interventions: intervention 1: ACT-774312 intervention 2: Placebo
Intervention descriptions: intervention 1: ACT-774312 will be available as hard gelatin capsules containing 200 mg of ACT-774312 intervention 2: Matching placebo hard gelatin capsules

Protocol documents:
Prot_SAP_000.pdf: 
Cover page 
 
Official Title:  
A Randomized, Double-blind, Placebo-controlled, 12-week Treatment Study to 
Evaluate the Effect of ACT-774312 in Subjects With Bilateral Nasal Polyposis 
 
ClinicalTrials.gov Identifier:  
NCT03688555 
 
Brief Title:  
A Study to Evaluate the Effect of ACT-774312 in Subjects With Bilateral Nasal 
Polyposis 
 
Date of protocol document:  
25 July 2019 
 












ACT-774312 
Nasal polyposis 
Protocol ID-084A201 
Final Version 3 
25 July 2019, page 6/103 
Confidential  
EudraCT: 2018-000851-42 
Doc No D-19.158 
 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
ACT-774312 
Indication 
Nasal polyposis 
Protocol number, title  
ID-084A201, A randomized, double-blind, placebo-controlled, 12-week treatment study to 
evaluate the effect of ACT-774312 in subjects with bilateral nasal polyposis 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form, and any other protocol-related documents. I fully understand that any 
changes instituted by the investigator(s) without previous agreement with the sponsor 
would constitute a violation of the protocol, including any ancillary studies or procedures 
performed on study subjects (other than those procedures necessary for the well-being of 
the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. In particular, I will obtain approval by an Independent 
Ethics Committee or Institutional Review Board (IEC/IRB) prior to study start and signed 
informed consent from all subjects included in this study. If an amendment to the protocol 
is necessary, I will obtain approval by an IEC/IRB and ensure approval by regulatory 
authorities (if applicable) has been obtained before the implementation of changes 
described in the amendment. In addition, I will allow direct access to source documents 
and study facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and 
agree to inspection by regulatory authorities or IEC/IRB representative(s). I will ensure 
that the study treatment(s) supplied by the sponsor are being used only as described in this 
protocol. Furthermore, I confirm herewith that the sponsor is allowed to enter and utilize 
my professional contact details and function in an electronic database for internal purposes 
and for submission to health authorities worldwide. 
Investigator 
 Site number 
 Date 
 Signature 


ACT-774312 
Nasal polyposis 
Protocol ID-084A201 
Final Version 3 
25 July 2019, page 7/103 
Confidential  
EudraCT: 2018-000851-42 
Doc No D-19.158 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
PROTOCOL SYNOPSIS ID-084A201 .............................................................................17 
1 
BACKGROUND AND RATIONALE .......................................................................33 
1.1 
Indication ......................................................................................................33 
1.2 
ACT-774312 .................................................................................................34 
1.2.1 
Nonclinical data ................................................................................34 
1.2.1.1 
Pharmacology ......................................................................... 34 
1.2.1.2 
Pharmacokinetics and metabolism ......................................... 35 
1.2.1.3 
Toxicology .............................................................................. 36 
1.2.2 
Effects in humans ..............................................................................37 
1.3 
Study rationale ..............................................................................................38 
1.3.1 
Medical and regulatory background .................................................38 
1.3.2 
Subject population ............................................................................40 
1.3.3 
Study design ......................................................................................41 
1.3.4 
Dose selection ...................................................................................41 
1.3.5 
Safety margin calculations, dose selection, and stopping 
criteria ...............................................................................................41 
1.3.6 
Comparator(s) and/or placebo ..........................................................43 
1.3.7 
Treatment duration ............................................................................43 
1.3.8 
Primary endpoint ...............................................................................43 
1.3.9 
Statistical hypotheses and sample size ..............................................43 
2 
STUDY OBJECTIVES ...............................................................................................43 
2.1 
Primary objective ..........................................................................................43 
2.2 
Secondary objectives ....................................................................................43 
3 
INVESTIGATIONAL PLAN .....................................................................................44 
3.1 
Overall study design and plan ......................................................................44 
3.1.1 
Screening and run-in period ..............................................................45 
3.1.2 
Treatment period ...............................................................................45 
3.1.3 
Post-treatment period ........................................................................45 
3.1.4 
End-of-Study .....................................................................................46 
3.1.5 
End of trial ........................................................................................46 
3.2 
Study population ...........................................................................................46 
3.2.1 
Subject population ............................................................................46 
3.2.2 
Inclusion criteria ...............................................................................46 


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3.2.3 
Exclusion criteria ..............................................................................47 
3.2.4 
Concomitant medications .................................................................49 
3.2.4.1 
Mandatory medications .......................................................... 49 
3.2.4.2 
Allowed medications .............................................................. 49 
3.2.4.3 
Forbidden medications ........................................................... 50 
3.2.5 
Dietary aspects, alcohol, smoking, physical activities ......................51 
3.3 
Study treatments ...........................................................................................51 
3.3.1 
Investigational treatment ...................................................................52 
3.3.2 
Placebo ..............................................................................................52 
3.4 
Packaging, labeling, and preparation ............................................................52 
3.4.1 
Labeling ............................................................................................52 
3.4.2 
Preparation ........................................................................................52 
3.5 
Randomization, treatment assignment, replacement, blinding, study 
treatment administration, storage, and dosing ..............................................52 
3.5.1 
Randomization code .........................................................................52 
3.5.2 
Treatment assignment .......................................................................53 
3.5.3 
Replacement policy ...........................................................................54 
3.5.4 
Blinding ............................................................................................54 
3.5.5 
Emergency procedure for unblinding ...............................................55 
3.5.6 
Study treatment administration .........................................................55 
3.5.7 
Storage and return of study treatment ...............................................56 
3.5.8 
Study treatment dosing scheme ........................................................57 
3.5.9 
Study treatment up- and down-titration ............................................57 
3.6 
Study treatment discontinuation and study discontinuation .........................58 
3.6.1 
Study treatment dose adjustment ......................................................58 
3.6.2 
Study treatment interruption or discontinuation ...............................58 
3.6.3 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................59 
3.6.4 
Subject’s follow-up after study treatment discontinuation ...............59 
3.6.5 
Study discontinuation .......................................................................59 
3.6.6 
Subject follow-up after study discontinuation ..................................60 
3.6.7 
Medical care of subjects after study completion / withdrawal 
from study .........................................................................................60 
3.7 
Study treatment exposure and compliance ...................................................60 
3.8 
Study endpoints ............................................................................................61 
3.8.1 
Efficacy endpoints ............................................................................61 
3.8.1.1 
Primary efficacy endpoint ...................................................... 62 
3.8.1.2 
Secondary efficacy endpoints ................................................. 62 
3.8.1.3 
Exploratory efficacy endpoints .............................................. 62 
3.8.2 
Safety and tolerability endpoints ......................................................62 


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3.8.2.1 
Safety and tolerability endpoints  derived variables ............ 63 
3.8.3 
Pharmacokinetic and pharmacodynamic endpoints ..........................63 
3.8.3.1 
Pharmacokinetic endpoints ..................................................... 63 
3.8.3.2 
Calculation of pharmacokinetic endpoints and 
assumptions ............................................................................ 63 
3.8.3.3 
Pharmacodynamic endpoints .................................................. 64 
3.9 
Study assessments .........................................................................................64 
3.9.1 
Efficacy assessments .........................................................................64 
3.9.1.1 
Nasal endoscopy ..................................................................... 64 
3.9.1.2 
CT scan ................................................................................... 65 
3.9.1.3 
UPSIT ..................................................................................... 66 
3.9.1.4 
Visual analog scales for symptoms ........................................ 67 
3.9.1.5 
Physician Global Assessment ................................................. 67 
3.9.1.6 
Patient questionnaires ............................................................. 68 
3.9.2 
Safety and tolerability assessments ...................................................69 
3.9.2.1 
Specific safety and tolerability assessments ........................... 69 
3.9.2.2 
Laboratory assessments .......................................................... 70 
3.9.3 
Pharmacokinetic and pharmacodynamic assessments ......................73 
3.9.3.1 
Pharmacokinetic assessments ................................................. 73 
3.9.3.2 
Pharmacodynamic assessments .............................................. 74 
3.9.4 
Baseline variables, previous and concomitant medications ..............75 
3.9.4.1 
Baseline demographics ........................................................... 75 
3.9.4.2 
Medical history ....................................................................... 75 
3.9.4.3 
Body mass index .................................................................... 75 
3.9.4.4 
Previous and concomitant medications .................................. 76 
3.9.4.5 
Immunoglobulin E titer .......................................................... 76 
3.9.4.6 
Spirometry .............................................................................. 76 
3.9.4.7 
Asthma Control Questionnaire ............................................... 76 
3.9.4.8 
Asthma Quality of Life Questionnaire ................................... 77 
3.10 
Visit and assessment schedule ......................................................................77 
3.10.1 
Sequence of assessments ..................................................................77 
3.10.2 
Total blood volume ...........................................................................78 
4 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................78 
4.1 
Adverse events ..............................................................................................78 
4.1.1 
Definitions of adverse events ............................................................78 
4.1.2 
Intensity of adverse events ................................................................79 
4.1.3 
Relationship to study treatment ........................................................80 
4.1.4 
Adverse events related to study design or protocol-mandated 
procedures .........................................................................................80 


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4.1.5 
Reporting of adverse events ..............................................................80 
4.1.6 
Follow-up of adverse events .............................................................81 
4.2 
Suspected unexpected serious adverse reactions ..........................................81 
4.3 
Serious adverse events ..................................................................................81 
4.3.1 
Definitions ........................................................................................81 
4.3.1.1 
Serious adverse events ............................................................ 81 
4.3.1.2 
Serious adverse events associated with the study design 
or protocol-mandated procedures ........................................... 82 
4.3.2 
Reporting of serious adverse events .................................................82 
4.3.2.1 
After the follow-up period ...................................................... 82 
4.3.2.2 
Reporting procedures ............................................................. 82 
4.3.3 
Follow-up of serious adverse events .................................................83 
4.4 
Pregnancy .....................................................................................................83 
4.4.1 
Teratogenicity ...................................................................................83 
4.4.2 
Reporting of pregnancy ....................................................................83 
4.4.3 
Follow-up of pregnancy ....................................................................84 
5 
STATISTICAL METHODOLOGY AND ANALYSES ............................................84 
5.1 
Statistical analysis plan .................................................................................84 
5.2 
Analysis sets .................................................................................................84 
5.3 
Primary endpoint ..........................................................................................85 
5.3.1 
Statistical model ................................................................................85 
5.3.2 
Hypotheses and statistical inference .................................................85 
5.3.3 
Primary endpoint analysis .................................................................85 
5.3.3.1 
Main analysis .......................................................................... 85 
5.3.3.2 
Confirmatory analyses ............................................................ 86 
5.3.4 
Primary endpoint display ..................................................................86 
5.4 
Secondary efficacy endpoints .......................................................................86 
5.4.1 
Secondary efficacy endpoint analysis ...............................................86 
5.4.2 
Secondary efficacy endpoint display ................................................86 
5.4.3 
Other efficacy endpoint display ........................................................86 
5.5 
Sample size ...................................................................................................87 
5.6 
Pharmacokinetic and pharmacodynamic endpoints .....................................87 
5.6.1 
Pharmacokinetic endpoints ...............................................................87 
5.6.2 
Pharmacodynamic endpoints ............................................................87 
5.7 
Safety and tolerability endpoints ..................................................................88 
5.7.1 
Adverse events ..................................................................................88 
5.7.2 
Vital signs .........................................................................................88 
5.7.3 
ECG recordings .................................................................................88 
5.7.4 
Clinical laboratory tests ....................................................................88 


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5.8 
Exposure to study treatment .........................................................................89 
5.9 
Baseline variables and concomitant medications .........................................89 
5.10 
Exploratory analyses .....................................................................................89 
5.11 
Interim analyses ............................................................................................89 
6 
PROCEDURES AND GOOD CLINICAL PRACTICE .............................................90 
6.1 
Procedures ....................................................................................................90 
6.1.1 
Protocol amendments ........................................................................90 
6.1.1.1 
Non-substantial amendment ................................................... 90 
6.1.1.2 
Substantial amendment ........................................................... 90 
6.1.1.3 
Urgent amendment ................................................................. 90 
6.1.2 
Monitoring ........................................................................................91 
6.1.3 
Data management .............................................................................92 
6.1.3.1 
Data collection ........................................................................ 92 
6.1.3.2 
Data management and quality control .................................... 93 
6.1.4 
Recording of data and retention of documents .................................94 
6.1.5 
Audit .................................................................................................95 
6.1.6 
Inspections ........................................................................................95 
6.1.7 
Handling of study treatment(s) .........................................................96 
6.1.8 
Publication and reporting of study results ........................................96 
6.1.9 
Disclosure and confidentiality ..........................................................97 
6.1.10 
Premature termination or suspension of the study ............................97 
6.2 
Good Clinical Practice ..................................................................................98 
6.2.1 
Ethics and Good Clinical Practice ....................................................98 
6.2.2 
Ethics Committee / Institutional Review Board ...............................98 
6.2.3 
Informed consent ..............................................................................98 
6.2.4 
Compensation to subjects and investigators .....................................99 
7 
REFERENCES ............................................................................................................99 
8 
APPENDICES ...........................................................................................................103 
 
 




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Nasal polyposis 
Protocol ID-084A201 
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LIST OF ABBREVIATIONS AND ACRONYMS 
ACQ  
Asthma Control Questionnaire 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
AQLQ  
Asthma Quality of Life Questionnaire with Standardised 
Activities 
AST  
Aspartate aminotransferase 
ATS  
All-treated set 
AUC  
Area under the plasma concentration-time curve 
AUC  
Area under the plasma concentration-time curve during a dose 
interval 
AUC0-4  
Area under the plasma concentration-time curve from zero to 4 h 
AUC0-t  
Area under the plasma concentration-time curve from zero to time 
t of the last measured concentration above the limit of 
quantification 
b.i.d.  
Twice daily 
  
 
BLQ  
Below the limit of quantification 
BMI  
Body mass index 
BP  
Blood pressure 
CDISC  
Clinical Data Interchange Standards Consortium 
CFR  
Code of Federal Regulations (US) 
CI  
Confidence interval 
Cmax  
Maximum plasma concentration 
CNS  
Central nervous system 
CRO  
Contract Research Organization 
CRS  
Chronic rhinosinusitis  
CRSsNP  
Chronic rhinosinusitis phenotype without nasal polyps 
CRSwNP  
Chronic rhinosinusitis phenotype with nasal polyps 
CRTH2  
Chemoattractant receptor-homologous molecule expressed on Th-2 
cells 


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CT  
Computed tomography 
CV  
Coefficient of variation 
CYP  
Cytochrome P450 
DBP  
Diastolic blood pressure 
DK-PGD2  
13,14-dihydro-15-keto-prostaglandin D2 
ECG  
Electrocardiogram/graphy 
eCRF  
Electronic Case Report Form 
EDC  
Electronic Data Capture 
ENT  
Ears, nose, and throat 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
FEV1  
Forced expiratory volume in 1 second 
FSH  
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GLP  
Good Laboratory Practice 
hCG   
Human chorionic gonadotropin  
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
i.v.  
Intravenous 
IB  
Investigator’s Brochure 
IC50  
Half maximum inhibitory concentration 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
ICS  
Inhaled corticosteroids 
IEC  
Independent Ethics Committee 
IgE  
Immunoglobulin E 
IL  
Interleukin 
ILC2 
 
Group 2 innate lymphoid cells 
IMP  
Investigational medicinal product 
INCS  
Intranasal corticosteroids 
IRB  
Institutional Review Board 


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ISF  
Investigator Site File 
K3-EDTA  
Tri-potassium ethylene diamine tetra-acetic acid  
LC-MS/MS  
Liquid chromatography with tandem mass spectrometry 
LOQ  
Limit of quantification 
MAD  
Multiple-ascending dose 
MAP  
Mean arterial pressure 
MDRP  
Multidrug-resistant protein-1 
MedDRA  
Medical Dictionary for Regulatory Activities 
MFNS  
Mometasone furoate nasal spray 
MMRM  
Mixed model for repeated measurements 
NOAEL  
No-observed-adverse-effect level 
NP  
Nasal polyposis 
NPS  
Nasal polyp score 
NSAID  
Nonsteroidal anti-inflammatory drug 
o.d.  
Once daily 
  
 
  
 
OCS  
Oral corticosteroids 
OMC  
Ostiomeatal complex 
p.o.  
Orally 
PD  
Pharmacodynamic(s) 
PGA 
 
Physician Global Assessment 
PGAC-DS  
Physician Global Assessment of Change in Disease Severity 
PGA-DS  
Physician Global Assessment of Disease Severity 
PGD2  
Prostaglandin D2 
PGIC-DS  
Patient Global Impression of Change in Disease Severity 
  
 
PK  
Pharmacokinetic(s) 
PPS  
Per-protocol set 
PT  
Preferred term 
QoL  
Quality of life 


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QTcB  
QT interval corrected with Bazett’s formula 
QTcF  
QT interval corrected with Fridericia’s formula 
RSI 
 Reference safety information 
SAD  
Single-ascending dose 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure 
SD  
Standard deviation 
SDTM  
Study Data Tabulation Model 
SE  
Standard error 
SNOT-22  
Sino-Nasal Outcome Test 
SOC  
System organ class 
SUSAR  
Suspected unexpected serious adverse reaction 
Th-2  
T helper 2 cell 
tmax  
Time to reach maximum plasma/blood concentration 
TMF  
Trial Master File 
ULN  
Upper limit of normal 
UPSIT  
University of Pennsylvania Smell Identification Test 
URL  
Upper Airways Research Laboratory 
US  
United States 
VAS  
Visual analog scale(s) 
WHO  
World Health Organization 
 
 


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Nasal polyposis 
Protocol ID-084A201 
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PROTOCOL SYNOPSIS ID-084A201 
TITLE 
A randomized, double-blind, placebo-controlled, 12-week 
treatment study to evaluate the effect of ACT-774312 in 
subjects with bilateral nasal polyposis. 
OBJECTIVES 
Primary objective 
To evaluate the effect of ACT-774312 on bilateral nasal 
polyposis (NP).  
Secondary objectives 
 To evaluate the safety and tolerability of ACT-774312 
during 12 weeks of treatment. 
 To evaluate the pharmacokinetics (PK) of ACT-774312 in 
subjects with NP. 
 To evaluate the pharmacodynamic (PD) responses to 
ACT-774312 based on T helper 2 cell (Th-2) biomarkers. 
DESIGN / PHASE 
Randomized, double-blind, 12-week, placebo-controlled, 
exploratory proof-of-concept Phase 2 study.  
STUDY PLANNED 
DURATION 
First subject 
First visit 
3Q18 
Last subject 
First visit 
3Q20 
Last subject 
Last visit 
4Q20 
CENTERS / 
COUNTRIES  
The study will be conducted in up to 4 sites in 4 countries 
SUBJECTS / GROUPS 24 subjects with bilateral NP: 
 16 subjects on ACT-774312 
 8 subjects on placebo. 
INCLUSION 
CRITERIA 
 Signed informed consent in the local language prior to any 
study-mandated procedure. 
 A minimum bilateral nasal polyp score (NPS) of 5 out of 
a maximum of 8 for both nostrils (with at least a score of 
2 for each nostril) despite completion of a prior intranasal 
corticosteroids (INCS) treatment for at least 8 weeks 
before screening, with at least the 6 last weeks on INCS 
spray. 


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 Presence of at least 2 of the following symptoms at 
screening:  
 nasal blockade/obstruction  
 nasal discharge (anterior/posterior nasal drip) 
 reduction or loss of smell 
 Male and female subjects aged between 18 and 70 years 
(inclusive) at screening. 
 Subjects with a body mass index ≥ 18 kg/m2. 
 Systolic blood pressure 90−160 mmHg, diastolic blood 
pressure 50−100 mmHg, and pulse rate 45−100 bpm 
(inclusive), measured on the dominant arm, after 5 min in 
the supine position at screening. 
 Women of childbearing potential must have a negative 
serum pregnancy test at screening and a negative urine 
pregnancy test pre-dose on Day 1. Women of childbearing 
potential must consistently and correctly use (from at least 
first dosing, during the entire study, and for at least 
30 days after last study treatment intake) 1 highly 
effective method of contraception with a failure rate of 
< 1% per year, be sexually abstinent, or have a 
vasectomized partner. Hormonal contraceptives must 
have been initiated at least 1 month before first study 
treatment administration. Women not of childbearing 
potential are defined as post-menopausal (i.e., amenorrhea 
for at least 1 year without an alternative medical cause 
confirmed by follicle-stimulating hormone > 40 mIU/mL 
at screening), or surgically or naturally sterile. 
 Ability to communicate well with the investigator in the 
local language, and to understand and comply with the 
requirements of the study. 
EXCLUSION 
CRITERIA 
 CYP2C9 poor metabolizer subject. 
 Subject 
with 
severe 
renal 
function 
impairment 
(≤ 29 mL/min/1.73 m2) which is defined by estimated 
glomerular filtration rate estimated at screening using the 
Modification of Diet in Renal Disease formula. 
 Subject with Sino-Nasal Outcome Test (SNOT-22) < 20. 


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 Subject who has taken other investigational drugs or 
prohibited therapy for this study within 3 months before 
screening or 5 half-lives, whichever is longer, or 
participation in more than 3 investigational drug studies 
within 1 year prior to screening. 
 Pregnant or lactating women. Women who intend to 
become pregnant during the study. 
 Known allergic reactions or hypersensitivity to the study 
treatment or drugs of the same class, or any of the 
excipients.  
 Subject with prohibited medication at screening without 
full wash-out period. 
 Subject who has required oral corticosteroids (OCS) 
within 2 months before screening or is scheduled to 
receive OCS during the study period for another 
condition. 
 Subject who has required INCS drops within 6 weeks 
before screening. 
 Subject who was injected with long-lasting activity 
corticosteroids within 3 months before screening or is 
scheduled to receive these during the study period for 
another condition. 
 Subject diagnosed with a parasitic infection. 
 Subject ever diagnosed with cancer. 
 Positive results from the HIV or hepatitis B or C serology 
at screening (except for vaccinated subject or subject with 
past and resolved hepatitis). 
 Subject 
who 
has 
received 
specific 
allergen 
immunotherapy within the previous 3 months. 
 Any circumstances or conditions, which, in the opinion of 
the investigator, may affect full participation in the study 
or compliance with the protocol. 
 Subject considered as vulnerable (e.g., sponsor or site 
employee, investigator subordinate, subject incapable of 
giving consent, subject committed to an institution by way 
of official or judicial order). 


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 Legal incapacity or limited legal capacity at screening. 
 Veins unsuitable for intravenous puncture on either arm 
(e.g., veins that are difficult to locate, access or puncture, 
veins with a tendency to rupture during or after puncture). 
 Subject who has undergone any nasal surgery within 
6 months before screening. 
 Subject with unstable NPS during the run-in period, i.e., 
altered score at Day 1 when compared to the screening 
NPS (assessed by the investigator). 
 Subjects with conditions / concomitant diseases making 
them non-evaluable for the primary efficacy endpoint 
such as: 
 Antrochoanal polyps. 
 Nasal septal deviation that occludes at least one 
nostril. 
 Acute sinusitis, nasal infection or upper respiratory 
infection at screening or in the 2 weeks before 
screening. 
 Ongoing rhinitis medicamentosa. 
 Churg-Strauss 
syndrome, 
Young’s 
syndrome, 
Kartagener’s 
syndrome 
or 
dyskinetic 
ciliary 
syndromes, cystic fibrosis. 
 Signs or a CT scan suggestive of allergic fungal 
rhinosinusitis. 
 Subjects with co-morbid asthma are excluded if: 
 Forced expiratory volume in one second ≤ 60% of 
predicted normal. 
OR 
 An exacerbation requiring systemic (oral and/or 
parenteral) steroid treatment or hospitalization 
(> 24 h) for treatment of asthma has occurred within 
3 months prior to screening. 
OR 
 They are on a dose higher than 1000 µg fluticasone or 
the equivalent of inhaled corticosteroids (ICS). 


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 Subject with short life expectancy (less than 6 months). 
 Concomitant severe diseases (e.g., active and inactive 
pulmonary tuberculosis, diabetes mellitus, etc.). 
 Subject 
with 
active 
autoimmune 
disease 
(e.g., 
Hashimoto’s thyroiditis, Graves’ disease, inflammatory 
bowel disease, primary biliary cirrhosis, systemic lupus 
erythematosus, multiple sclerosis, psoriasis vulgaris, 
rheumatoid arthritis). 
 Subject with liver injury related criteria: 
 Underlying hepatobiliary disease 
OR 
 Alanine aminotransferase > 3  upper limit of normal 
(ULN) 
OR 
 Bilirubin > 2  ULN 
 Subject with evidence of acute or chronic infection: 
Visit 1 or Visit 2 oral temperature > 38 °C, a chronic 
persistent or recurring infection requiring active treatment 
with antibiotics, antivirals or antifungals within 4 weeks 
prior to the screening visit, or other frequent recurrent 
infections as per investigator judgment. 
 Subject with any contraindications or warning/precaution 
of use related to mometasone furoate nasal spray (MFNS) 
as described in the Summary of Product Characteristics. 
CONCOMITANT 
MEDICATIONS 
Mandatory from screening up to End-of-Study (EOS) 
 MFNS from screening to EOS as standard background 
therapy. 
 Mandatory therapy includes any treatments required for 
contraception purposes in women of childbearing 
potential. 
Prohibited from screening up to EOS 
 Use of intranasal medication that would interfere with the 
symptoms 
of 
diseases 
(antihistamines, 
atropine, 
ipratropium bromide, cromolyn), except normal saline 
solution. 




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anesthetics, e.g., lidocaine, are only allowed before 
endoscopy. 
 Short-term use of antibiotics (< 2 weeks).  
 For subjects with asthma: 
 Short- and long-acting beta-agonists. 
 Methylxanthines (e.g., theophylline and 
aminophyllines). 
 ICS on a stable daily dose ≤ 1000 µg fluticasone (or 
the equivalent dose of another ICS) only for subjects 
that were on a stable dose for ≥ 30 days prior to 
screening). 
 Leukotriene antagonists/modifiers if subject is on 
continuous treatment for at least 30 days prior to 
screening. 
 Initiation 
of 
allergen 
immunotherapy 
(allergen 
immunotherapy in place for ≥ 3 months prior to Visit 1 is 
permitted). 
 Medications needed for the treatment of adverse events 
(AEs) and which are not prohibited. 
 Hormonal contraceptives. 
STUDY PERIODS 
The clinical trial will be divided into 3 periods: 
Screening and run-in period: (4 weeks  2 days) 
This period will start with the screening visit (Visit 1) and will 
end on Day 1 (Visit 2) just before the first ACT-774312 
administration. 
At screening, subjects must have been on a stable regimen of 
INCS for at least 8 weeks. 
If a subject is using an INCS product different from MFNS 
prior to the screening visit, the investigator must switch the 
patient to MFNS at screening. 
At Visit 1, all subjects will enter a run-in period of 4 weeks 
on MFNS of 2 actuations (50 μg/actuation) in each nostril 
twice daily (b.i.d.), total daily dose of 400 μg, unless they are 


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intolerant to b.i.d. INCS in which case they may use a lower 
dose regimen, i.e., once daily (o.d.). 
Treatment period: (ACT-774312/placebo for 12 weeks) 
This period will start on Day 1 after the first administration of 
ACT-774312 and will consist of 4 visits: Visit 3 (Week 2), 
Visit 4 (Week 4), Visit 5 (Week 8), and Visit 6 (Week 12). 
Provided that the NPS does not change during the run-in 
period, subjects will be randomized to one of the following 
treatments: 
 ACT-774312 400 mg b.i.d. for 12 weeks. 
 Placebo b.i.d. for 12 weeks. 
During the double-blind randomized treatment: 
All subjects will continue MFNS (200 μg) either b.i.d. or o.d. 
over the treatment period with the investigational medicinal 
product (IMP). 
Post-treatment period  
This period will start after Visit 6 (Week 12) and will end at 
Visit 7 (Week 16). 
After completing 12 weeks of study treatment, subjects will 
be instructed to: 
 Continue on MFNS stable dose.  
 Contact the investigator if the symptoms worsen and 
require medical attention. 
 Report any AEs / serious AEs (SAEs). 
The end of the post-treatment period constitutes the EOS. 
Subjects who discontinue prematurely from study treatment 
will be recommended to continue with the study assessments 
up to EOS or at least perform EOS visit 38 days (+2 days) 
after study treatment discontinuation. 


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STUDY TREATMENT 
ACT-774312 
ACT-774312 will be administered orally as 400 mg b.i.d. for 
12 weeks. Subjects will receive 2  200 mg capsules in the 
morning and evening, with or without food. 
Placebo 
Matching ACT-774312 placebo capsules. 
Non-IMP (standard background therapy) 
MFNS (
 50 μg/actuation nasal spray, suspension. 
Dosing regimen: 2 actuations (50 μg/actuation) in each nostril 
b.i.d. (or o.d. if b.i.d. is not tolerated). 
EFFICACY 
ENDPOINTS 
Baseline: Defined as the last value measured prior to first 
intake of study treatment. 
Primary endpoint 
 Change from baseline to Week 12 in NPS as measured by 
nasal endoscopy assessed centrally. 
Secondary endpoints 
 Change from baseline to Week 12 in sinus opacifications 
as assessed by CT scan using the Zinreich-modified 
Lund-Mackay score assessed centrally. 
 Change from baseline to Week 12 in 3D volumetric 
computerized values. 
 Change from baseline to Weeks 2, 4, 8, 12, and EOS in 
University of Pennsylvania Smell Identification Test. 
 Change from baseline to Weeks 2, 4, 8, 12, and EOS in 
the sum of visual analog scale symptom scores for nasal 
obstruction, nasal discharge, mucus in the throat, loss of 
smell, and facial pain. 
 Change from baseline to Weeks 2, 4, 8, 12, and EOS in 
Physician Global Assessment score. 
 Change from baseline to Weeks 2, 4, 8, 12, and EOS in 
SNOT-22. 
 Patient global impression of change in disease severity at 
Weeks 2, 4, 8, 12, and EOS.  


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TOLERABILITY / 
SAFETY ENDPOINTS 
Baseline: Defined as the last value measured prior to first 
intake of study treatment. 
 Change from baseline to Weeks 2, 4, 8, 12, and EOS in 
vital sign (supine) measurements. 
 Change from baseline to EOS in body weight 
measurement. 
 Change from baseline to End-of-Treatment (EOT) in ECG 
variable measurements: heart rate, and the intervals: 
PQ/PR, QRS, QT, RR, QT interval corrected with 
Bazett’s formula, and QT interval corrected with 
Fridericia’s formula. 
 Treatment-emergent# ECG abnormalities at EOT.  
 Change from baseline to Weeks 2, 4, 8, 12, and EOS in 
clinical laboratory tests.  
 Treatment-emergent AEs up to EOS. 
 Treatment-emergent SAEs up to EOS. 
 AEs leading to premature discontinuation of study 
treatment up to EOT. 
 Treatment discontinuation due to systemic corticosteroids 
administration for NP and/or surgery for nasal polyps 
before Week 12. 
# Treatment-emergent is defined from first study treatment administration 
up to EOS. 
PHARMACOKINETIC/ 
PHARMACODYNAMIC 
ENDPOINTS 
Pharmacokinetics 
The plasma PK parameters of ACT-774312 at Week 2 will be 
derived by non-compartmental analysis of the plasma 
concentration-time profile.  
Maximum plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) values are assumed 
to be log-normally distributed. 
Pharmacokinetic endpoints 
 Trough ACT-774312 concentration at Weeks 2, 4, 8, and 
12. 




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All-treated set (ATS): 
This analysis set includes all randomized subjects who 
received at least one dose study treatment. 
Per-protocol set (PPS): 
This analysis set includes all randomized subjects who 
completed the treatment up to Week 12 without protocol 
deviations that may affect the evaluation the primary 
endpoints (to be defined the statistical analysis plan [SAP]).  
The target number of subjects in the PPS is 21. If this number 
is unlikely to be reached, the number of subjects to be 
randomized may be increased over 24. 
Pharmacokinetic set: 
This analysis set comprises all subjects from the ATS who 
completed treatment with ACT-774312 at least up to Week 2 
without protocol deviations that may affect the evaluation of 
the PK endpoints. 
Pharmacodynamic set: 
This analysis set comprises all subjects from the ATS who 
completed treatment with ACT-774312 or placebo at least up 
to Week 2 without protocol deviations that may affect the 
evaluation of the PD endpoints. 
Analysis of the primary endpoint 
The primary analysis will be conducted on the PPS. All NPS 
values observed between baseline and Week 12 will be 
included in this analysis. 
Changes from baseline to post-baseline visits in NPS will be 
analyzed using a mixed model for repeated measurements 
(MMRM) with factors for treatment group, study site, visit, 
treatment by visit interaction and covariates for baseline NPS, 
and the interaction between baseline NPS and visit. An 
unstructured covariance matrix will be used to account for the 
correlation between repeated measurements from the same 
subject. 


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Estimation of the treatment difference for the primary 
endpoint, change from baseline to Week 12 in NPS, will be 
based on the mixed model.  
Missing data handling in the primary analysis 
All subjects in the PPS are expected to have a Week 12 NPS. 
Any intermediate missing data will be handled by the mixed 
model. Missing values will not be imputed. 
Sensitivity analyses 
A sensitivity analysis will be conducted on the ATS using the 
same mixed model as for the primary analysis. In this 
approach missing values will not be imputed, but will be 
handled by the model assuming that the data are missing at 
random. Additionally, an analysis of covariance (ANCOVA) 
will be performed for the change from baseline to Week 12 in 
NPS with missing data imputed using last observation carried 
forward. 
Analysis of secondary endpoints 
Change from baseline to Week 12 in Zinreich-modified 
Lund-Mackay score will be analyzed using an ANCOVA 
model with a factor for treatment group and a covariate for the 
baseline score. Other continuous endpoints will be 
summarized by time point and treatment group using 
descriptive statistics. Some secondary endpoints (to be 
defined in the SAP) will also be analyzed using the same 
MMRM as for the primary endpoint. 
Tolerability and safety analyses 
Safety analyses will be conducted on the ATS. The treatment-
emergent period for the safety assessments is defined as the 
time from the first administration of study treatment to Visit 7 
(Week 16). 
Tolerability and safety data will be summarized by treatment 
group using descriptive statistics. 
Analysis of PK and PD endpoints 
The PK set and PD set will be used for analysis of the PK and 
PD endpoints, respectively. 


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PK parameters will be derived using non-compartmental 
methods. 
PK and PD endpoints will be analyzed descriptively. 
 


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Table 1 
Visit and assessment schedule 
 
Screening/Run-in 
Treatment 
EOT 
Post-Treatment EOS 
Visit 
1 
2 
3 
4 
5 
6 
7 
Study Week (Days) 
–4 (Day –30  
to Day –26) 
0 (Day 1) 
2 (Day 12 to 
Day 16) 
4 (Day 26 to 
Day 30) 
8 (Day 54 to 
Day 58) 
12 (Day 81 to 
Day 84) 
16 (Day 111 to 
Day 116) 
Informed consent 
X 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
Previous/Concomitant 
medications 
X1 
X4 
X 
X 
X 
X 
X 
Physical examination 
X 
X4 
 
 
 
X 
X 
cyp2c9 genotyping 
X 
 
 
 
 
 
 
ACQ8 and AQLQ8 
X 
 
 
 
 
 
 
IgE titer 
X 
 
 
 
 
 
 
Serum pregnancy test2 
X 
X4, 7 
X7 
X7 
X7 
X7 
X7 
Body weight and height3 
X 
 
 
 
 
 
X 
Virus serology 
X 
 
 
 
 
 
 
Spirometry8 
X 
 
 
 
 
 
 
Vital signs (BP and pulse rate) 
X 
X4 
X 
X 
X 
X 
X 
12-lead ECG 
 
X4 
 
 
 
X 
 
Hematology 
X 
X4 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
X4 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X4 
X 
X 
X 
X 
X 
MFNS5 
 
 
 
 
 
 
 
Study treatment5 
 
 
 
 
 
 
 
Nasal endoscopy 
X 
X4 
 
X 
X 
X 
X 
CT scan 
 
X4 
 
 
 
X 
 
VAS score 
 
X4 
X 
X 
X 
X 
X 
UPSIT 
 
X4 
X 
X 
X 
X 
X 
SNOT-22 
X 
X4 
X 
X 
X 
X 
X 




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1 BACKGROUND AND RATIONALE 
1.1 Indication 
Chronic rhinosinusitis (CRS) is defined as an inflammation of the nose and paranasal 
sinuses, characterized by two or more symptoms, one of which should be nasal blockage 
or nasal discharge and/or facial pain or pressure and/or reduction or loss of smell 
[Fokkens 2012]. The presence (CRSwNP) or absence (CRSsNP) of nasal polyps based on 
results from endoscopy and computed tomography (CT) is a critical item to phenotype 
CRS. Additional subtypes can, however, be identified based on underlying conditions, such 
as allergic fungal rhinosinusitis, CRS associated with acetylsalicylic acid-exacerbated 
respiratory disease, CRS in patients with cystic fibrosis, primary ciliary dyskinesia, 
systemic diseases, or immune deficiency (all present in CRSwNP or CRSsNP) 
[Bachert 2015]. Additionally, subjects might have comorbidities, such as inhalant allergies 
and asthma (30% of patients with CRSwNP). 
Nasal polyposis (NP) is a clinical condition characterized by the presence of multiple 
polyps in the upper nasal cavity, originating from the ostiomeatal complex (OMC). Up to 
4% of the general population is estimated to be affected by nasal polyps [Lange 2013]. 
Symptoms experienced by patients with NP include nasal blockage, loss of smell, 
rhinorrhea, and symptoms derived from lower airway involvement [Alobid 2005]. Nasal 
polyps often have a deleterious effect on many aspects of quality of life (QoL), including 
physical health, general health, social functioning, sleep, and mental health [Erskine 2016, 
Hoehle 2016, Rudmik 2011]. 
Recent efforts to better characterize the pathophysiology of CRS has led to a refined 
classification by endotype [Bachert 2016a, Avdeeva 2018]. The latter can be differentiated 
on cells involved, such as by the abundance of eosinophils or neutrophils, on T helper cell 
populations or levels of immunoglobulin E (IgE) or cytokines, including interleukin (IL)-4, 
IL-5, or IL-13. 
As an example, mucosal eosinophilia exhibits significant geographic and ethnic 
differences. In Europe and in the US, the most prevalent endotype in CRSwNP presents a 
type 2 inflammatory response [Mygind 2000] and is characterized by high prevalence of 
eosinophils, mast cells, with elevated type 2 cytokines (IL-4, IL-5, IL-9, IL-13, IL-25, and 
IL-33), and Th2 cells. In contrast, in East Asia, this eosinophilic endotype constitutes less 
than half of the CRSwNP cases [Cao 2009]. 
Current treatment options for patients with NP are not based on endotypes, and are limited 
to intranasal and oral corticosteroids, long-term antibiotics and surgery [Sharma 2014, 
Van Zele 2010, Fokkens 2012]. Intranasal corticosteroids (INCS) are usually the initial 
treatment for nasal polyps, with good outcomes for patients with mild NP [Kalish 2012]. 
The use of systemic corticosteroids is reserved for more severe cases but due to the side 










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concentration (12 h post-dose) when ACT-774312 was given concomitantly with a 
high-fat, high-calorie breakfast. As the goal is to maintain CRTH2 blockade over the full 
dosing interval, ACT-774312 trough concentration is a critical parameter. ACT-774312 
can therefore be administered with or without food. 
ACT-774312 fully blocked CRTH2 at the surface of eosinophils for at least 9 h post-dose 
at 50 mg b.i.d. The Emax model indicated that ACT-774312 was able to maintain 90% of 
CRTH2 blockade over the full dosing interval in 80% of healthy subjects at a dose of 
110 mg b.i.d. 
Neither severe nor serious adverse events (SAEs) were reported. The most frequent adverse 
events (AEs) observed following multiple-dose intake of ACT-774312 were headache and 
dizziness. No clinically relevant effects on vital signs, laboratory variables, or 12-lead ECG 
were observed. 
More detailed information can be found in the Investigator’s Brochure (IB) 
[ACT-774312 IB]. 
1.3 Study rationale 
NP is a Th-2-driven inflammatory process in which eosinophils are the predominant 
inflammatory cells found in the sinuses and nasal polyps. ACT-774312 is an antagonist of 
CRTH2 which is expressed on the surface of blood-borne cells that play a central role in 
allergy and type-2 inflammation: eosinophils, basophils, mast cells, ILC2, and Th-2 cells. 
Therefore, ACT-774312 might reduce the inflammatory process involved in NP. 
1.3.1 Medical and regulatory background 
This study is a proof-of-concept Phase 2 study designed to assess the effects of 
ACT-774312 on bilateral NP. In addition, tolerability, safety, PK, and PD of ACT-774312 
in this population will be investigated. 
Risk-benefit assessment 
In Europe and in the US, the most prevalent endotype in CRSwNP presents a type 2 
inflammatory response [Mygind 2000] and is characterized by high prevalence of 
eosinophils, mast cells, and Th-2 cells, with elevated type 2 cytokines (IL-4, IL-5, IL-9, 
IL-13, IL-25, and IL-33), in NP. Recent clinical studies with monoclonal antibodies against 
IL-5 (reslizumab and mepolizumab [Gevaert 2011, Bachert 2017]) or against IL-4 receptor 
α (dupilumab [Bachert 2016b]) have shown improvement of CRSwNP symptoms 
combined with significant reduction of polyp and computed tomography scores. Therefore, 
it is expected that ACT-774312, by targeting the type 2 inflammatory pathway like the 
monoclonal antibodies, has the potential to be effective in the treatment of patients 
suffering from diseases with a Th-2-associated allergic etiology, including NP. 




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laboratory variables, or 12-lead ECG were observed up to 1000 mg and 500 mg b.i.d. for 
4 days in the SAD and MAD parts, respectively. Therefore, based on the limited 
information available from healthy subjects receiving ACT-774312 in this study, no safety 
concerns have been identified. Steady-state conditions are reached on the second day of 
b.i.d. treatment, therefore no additional safety concerns are expected with a 12-week 
treatment period compared to the 4-day treatment of the MAD. In addition, there are no 
specific safety concerns due to potential class effects based on the experience with other 
CRTH2 antagonists currently in late-stage development (mainly for the treatment of 
asthma and allergic rhinitis) [Norman 2014, Ratner 2017]. 
Due to the absence of data in patients with renal function impairment and hepatic function 
impairment, these will be excluded from the study. NP is not considered a life-threatening 
disease with irreversible morbidity if not treated immediately. It is hence considered 
acceptable and ethical to include a placebo-treated arm in a clinical study of subjects with 
NP [ICH 2000]. Subjects will be aware of the probability of being assigned to the placebo 
arm and of the therapeutic alternatives. 
No particular safety concern related to the concomitant administration of ACT-774312 and 
mometasone furoate nasal spray (MFNS) is expected. Subjects with any contraindications 
or warning/precaution of use related to MFNS, as described in the Summary of Product 
Characteristics, will be excluded from the study [see 
]. 
In conclusion, based on available data on ACT-774312, the expected risk-benefit 
assessment supports the conduct of the proposed ID-084A201 study in subjects with 
bilateral NP. Exclusion criteria, safety monitoring activities, and strict medical 
management will further ensure the safety of the subjects included in the trial. 
1.3.2 Subject population 
The study population of ID-084A201 will consist of subjects with a physician endoscopic 
diagnosis of bilateral NP (nasal polyp score [NPS] of ≥ 5, with a minimum of 2 in each 
nostril) despite having completed a prior INCS treatment for at least 8 weeks before 
screening, with at least the 6 last weeks on INCS spray. A bilateral score of 5 is the standard 
grade at which INCS is not able to reduce the NPS further. 
In this study, ACT-774312 will be administered on top of MFNS, see the Summary of 
Product Characteristics 
. 
Taking the high co-morbidity of NP with asthma, chronic sinusitis, and previous surgeries 
into account, these subjects will be allowed to enter the study unless they meet any of the 
exclusion criteria described in Section 3.2.3. 


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1.3.3 Study design 
The study is a randomized, double-blind, 12-week treatment, placebo-controlled, 
exploratory proof-of-concept study evaluating the effect of 400 mg ACT-774312 
administered b.i.d. for 12 weeks. 
The clinical study consists of three periods: 
 Run-in period on MFNS for 4 weeks. 
 Treatment period (12 weeks). 
 Post-treatment period (30 days). 
The study is double-blind to avoid the bias incurred by an unblinded design on safety and 
efficacy assessments. Both the subject and investigator are blinded to the assigned study 
treatments. The study is placebo-controlled to provide a control group to which efficacy 
and safety can be compared. 
A 2:1 randomization ratio was chosen to obtain more information on ACT-774312. This 
unequal randomization ratio is only 6% less precise than a 1:1 ratio (as measured by the 
standard error [SE] of the mean difference). 
1.3.4 Dose selection  
The selection of the dose is based on the tolerability, safety, and PK/PD data from the 
completed entry-into-man study. In that study, doses of ACT-774312 up to 1000 mg and 
500 mg b.i.d. were administered in the SAD and MAD part, respectively. 
The dose in this Phase 2 study will be an intermediate dose of those investigated in the 
MAD study, namely, a 400 mg b.i.d. dose of ACT-774312. This dose is anticipated to 
maintain a 90% blockade of CRTH2 over the full dosing interval. In the AC-084-101 study, 
PK/PD modeling predicted that 110 mg b.i.d. ACT-774312 would be able to fully block 
ex vivo the agonist effect of 300 nM of DK-PDG2 in whole blood. 
1.3.5 Safety margin calculations, dose selection, and stopping criteria 
The safety margins calculated by comparing the plasma exposure in animals at the NOAEL 
with the human exposure after multiple-dose administration of 500 mg are shown in 
Table 2. The dose of 500 mg b.i.d. of ACT-774312 is the closest dose for which actual PK 
data are available. 




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1.3.6 Comparator(s) and/or placebo 
In this study, ACT-774312 will be compared to placebo. Both study treatments will be 
administered on top of standard background therapy: MFNS. 
1.3.7 Treatment duration 
The study treatment duration will be 12 weeks. This period has been proven sufficient to 
observe significant change in NPS [Gevaert 2011]. 
1.3.8 Primary endpoint 
The primary endpoint is the change from baseline at Week 12 in bilateral NPS.  
Bilateral NPS is an objective endpoint commonly used to evaluate the effect of medications 
or surgery in NP at the early stage of clinical development. 
The secondary efficacy endpoints, including symptom evaluations required as co-primary 
endpoint in later stages of development, are measured to more comprehensively evaluate 
the efficacy of ACT-774312. This study will also explore the improvement of NP and 
associated sinus inflammation on a CT scan, and improvement in condition with specific 
and general medical questionnaires to obtain a better understanding of the impact of NP on 
the subjects’ QoL.  
These endpoints, together with the biomarkers analysis, will provide information on the 
therapeutic value of ACT-774312 to reduce the NPS and to improve symptoms in NP. 
1.3.9 Statistical hypotheses and sample size 
Statistical hypotheses will not formally be tested in the estimation study. Thus, no formal 
sample size calculation was performed. Twenty-four subjects (16 in the ACT-774312 
group and 8 in the placebo group) provide a certain precision to estimate the treatment 
difference in the mean change from baseline in NPS [see Section 5.5].  
2 
STUDY OBJECTIVES 
2.1 Primary objective  
To evaluate the effect of ACT-774312 on bilateral NP. 
This primary objective will be assessed by several endpoints including the change from 
baseline to Week 12 in NPS assessed by endoscopy (the primary endpoint) as well as 
secondary endpoints assessed by CT, University of Pennsylvania Smell Identification Test 
(UPSIT), Sino-Nasal Outcome Test (SNOT-22), Physician Global Assessment (PGA), 
visual analog scales (VAS), and patient global impression of change in disease severity. 
2.2 Secondary objectives 
 To evaluate the safety and tolerability of ACT-774312 during 12 weeks of treatment. 


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 To evaluate the PK of ACT-774312 in subjects with NP. 
 To evaluate the PD responses to ACT-774312 based on Th-2 biomarkers. 
3 
INVESTIGATIONAL PLAN 
3.1 Overall study design and plan  
This is a randomized, double-blind, 12-week treatment, placebo-controlled, exploratory 
proof-of-concept study to evaluate the effect of ACT-774312 400 mg b.i.d. for 12 weeks 
in subjects with bilateral NP. 
The study will be conducted at up to 4 sites in 4 countries. 
Approximately 24 adult subjects will be randomized in a 2:1 ratio to either ACT-774312 
(approximately 16 subjects) or placebo (approximately 8 subjects). 
The clinical study will consist of 3 periods: 
 Run-in period: from screening to the end of run-in period (4 weeks). 
 Treatment period: from randomization to Visit 6 (12 weeks). 
 Post-treatment period: after Visit 6 to Visit 7 (30 days). 
The total duration of the study participation for each patient is up to 20 weeks. 
Figure 1 
Study design 
 
400 mg ACT-774312 + MFNS 
 
 
 
 
MFNS 
 
MFNS 
 
Placebo + MFNS 
 
Run-in 
Treatment period 
Post-treatment period 
4 weeks 
2 weeks 2 weeks 
4 weeks 
4 weeks 
4 weeks 
 
Visit 1                 Visit 2   Visit 3  Visit 4                Visit 5                   Visit 6                         Visit 7 
Screening       Randomization                                                                           EOT                                EOS 
EOS = End-of-Study; EOT = End-of-Treatment; MFNS = mometasone furoate nasal spray. 
 


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3.1.1 Screening and run-in period 
This period will start with the screening visit (Visit 1) and will end on Day 1 (Visit 2) just 
before the first ACT-774312/placebo administration. 
At screening, subjects must have been on a stable regimen of INCS for at least 8 weeks. 
If the subject is using an INCS product different from MFNS prior to the screening visit, 
the investigator must switch the subject to MFNS at screening.  
At Visit 1, all subjects will enter a run-in period of 4 weeks on MFNS of 2 actuations 
(50 μg/actuation) in each nostril b.i.d., total daily dose of 400 μg, unless they are intolerant 
to b.i.d. INCS in which case they may use a lower dose regimen, i.e., o.d. 
It is permitted to re-screen subjects once if the reason for non-eligibility was transient (e.g., 
insufficient washout period of a forbidden medication, etc.).  
3.1.2 Treatment period 
This period will start on Day 1 after the first administration of ACT-774312/placebo and 
will consist of 4 visits: Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 8), and Visit 6 
(Week 12). 
Provided that the NPS does not change during the run-in period, subjects will be 
randomized to one of the following study treatments: 
 ACT-774312 400 mg b.i.d. for 12 weeks. 
 Placebo b.i.d. for 12 weeks. 
During the double-blind randomized treatment period, all subjects will continue MFNS 
(200 μg) either b.i.d. or o.d. in addition to the investigational medicinal product (IMP). 
The End-of-Treatment (EOT) will take place at Visit 6 (or earlier in the event of premature 
discontinuation) between Day 81 and Day 84 to ensure subjects will still be receiving the 
study treatment. 
3.1.3 Post-treatment period 
The post-treatment period will start after Visit 6 (Week 12) and will end at Visit 7 
(Week 16). 
After completing the 12 weeks of study treatment or after premature discontinuation, 
subjects will be instructed to: 
 Continue their MFNS stable dose. 
 Contact the investigator if the symptoms worsen and require medical attention. 
  Report any AE/SAE. 


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The end of the post-treatment period constitutes the End-of-Study (EOS). 
3.1.4 End-of-Study 
The EOS examination will take place at Visit 7 (30 days +2 days after EOT (last study drug 
intake). At this visit, the subjects will undergo efficacy, tolerability, and safety assessments.  
Subjects who discontinue prematurely from the study treatment will be recommended to 
continue with the study assessments up to EOS or at least perform the EOS visit 30 days 
(+2 days) after study treatment discontinuation.  
3.1.5 End of trial 
The end of the complete trial is defined as the last subject last visit. 
3.2 Study population 
3.2.1 Subject population 
The subjects will have to present bilateral NP (NPS of at least 5 out of 8) assessed by a 
physician endoscopic diagnosis despite having completed a prior INCS treatment for at 
least 8 weeks, with at least the 6 last weeks on INCS spray. 
Subjects with an NPS of at least 5 will be approached to participate in the study. However, 
randomization to the study treatment will require that the NPS does not change during the 
run-in period as per local endoscopic assessment. 
3.2.2 Inclusion criteria  
Eligible subjects must meet all of the following inclusion criteria:  
 Signed informed consent in the local language prior to any study-mandated procedure.  
 A minimum bilateral NPS of 5 out of a maximum of 8 for both nostrils (with at least a 
score of 2 for each nostril) despite completion of a prior INCS treatment for at least 
8 weeks before screening, with at least the 6 last weeks on INCS spray. 
 Presence of at least 2 of the following symptoms at screening:  
 nasal blockade/obstruction. 
 nasal discharge (anterior/posterior nasal drip). 
 reduction or loss of smell. 
 Male and female subjects aged between 18 and 70 years (inclusive) at screening. 
 Subjects with a body mass index (BMI) ≥ 18 kg/m2. 
 SBP 90−160 mmHg, DBP 50−100 mmHg, and pulse rate 45−100 bpm (inclusive), 
measured on the dominant arm, after 5 min in the supine position at screening. 


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 Women of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test pre-dose on Day 1. Women of 
childbearing potential must consistently and correctly use (from at least first dosing, 
during the entire study, and for at least 30 days after last study treatment intake) 
1 highly effective method of contraception with a failure rate of < 1% per year, be 
sexually abstinent, or have a vasectomized partner. Hormonal contraceptives must have 
been initiated at least 1 month before first study treatment administration. Women not 
of childbearing potential are defined as post-menopausal (i.e., amenorrhea for at least 
1 year without an alternative medical cause confirmed by FSH > 40 mIU/mL at 
screening), or surgically or naturally sterile. 
 Ability to communicate well with the investigator in the local language, and to 
understand and comply with the requirements of the study. 
3.2.3 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria:  
 CYP2C9 poor metabolizer subject. 
 Subject with severe renal function impairment (≤ 29 mL/min/1.73 m2) which is defined 
by estimated glomerular filtration rate estimated at screening using the Modification of 
Diet in Renal Disease formula. 
 Subject with SNOT-22 < 20. 
 Subject who has taken other investigational drugs or prohibited therapy for this study 
within 3 months before screening or 5 half-lives, whichever is longer, or participation 
in more than 3 investigational drug studies within 1 year prior to screening. 
 Pregnant or lactating women. Women who intend to become pregnant during the study. 
 Known allergic reactions or hypersensitivity to the study treatment or drugs of the same 
class, or any of the excipients.  
 Subject with prohibited medication at screening without full wash-out period. 
 Subject who has required oral corticosteroids (OCS) within 2 months before screening 
or is scheduled to receive OCS during the study period for another condition. 
 Subject who has required INCS drops within 6 weeks before screening. 
 Subject who was injected with long-lasting activity corticosteroids within 3 months 
before screening or is scheduled to receive these during the study period for another 
condition. 
 Subject diagnosed with a parasitic infection. 


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 Subject ever diagnosed with cancer. 
 Positive results from the HIV or hepatitis B or C serology at screening (except for 
vaccinated subject or subject with past and resolved hepatitis). 
 Subject who has received specific allergen immunotherapy within the previous 
3 months. 
 Any circumstances or conditions, which, in the opinion of the investigator, may affect 
full participation in the study or compliance with the protocol. 
 Subject considered as vulnerable (e.g., sponsor or site employee, investigator 
subordinate, subject incapable of giving consent, subject committed to an institution by 
way of official or judicial order). 
 Legal incapacity or limited legal capacity at screening. 
 Veins unsuitable for i.v. puncture on either arm (e.g., veins that are difficult to locate, 
access or puncture, veins with a tendency to rupture during or after puncture). 
 Subject who has undergone any nasal surgery within 6 months before screening. 
 Subject with unstable NPS during the run-in period, i.e., altered score at Day 1 when 
compared to the screening NPS (assessed locally by the investigator). 
 Subjects with conditions / concomitant diseases making them non-evaluable for the 
primary efficacy endpoint such as: 
 Antrochoanal polyps. 
 Nasal septal deviation that occludes at least one nostril. 
 Acute sinusitis, nasal infection or upper respiratory infection at screening or in the 
2 weeks before screening. 
 Ongoing rhinitis medicamentosa. 
 Churg-Strauss syndrome, Young’s syndrome, Kartagener’s syndrome or dyskinetic 
ciliary syndromes, cystic fibrosis. 
 Signs or a CT scan suggestive of allergic fungal rhinosinusitis. 
 Subjects with co-morbid asthma are excluded if: 
 Forced expiratory volume in one second (FEV1) ≤ 60% of predicted normal. 
OR 
 An exacerbation requiring systemic (oral and/or parenteral) steroid treatment or 
hospitalization (> 24 h) for treatment of asthma has occurred within 3 months prior 
to screening. 


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OR 
 They are on a dose higher than 1000 µg fluticasone or the equivalent of inhaled 
corticosteroids (ICS) [see Appendix 1]. 
 Subject with short life expectancy (less than 6 months). 
 Concomitant severe diseases (e.g., active and inactive pulmonary tuberculosis, diabetes 
mellitus, etc.). 
 Subject with active autoimmune disease (e.g., Hashimoto’s thyroiditis, Graves’ 
disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus 
erythematosus, multiple sclerosis, psoriasis vulgaris, rheumatoid arthritis). 
 Subject with liver injury related criteria at Visit 1: 
 Underlying hepatobiliary disease 
OR 
 Alanine aminotransferase (ALT) > 3  upper limit of normal (ULN) 
OR 
 Bilirubin > 2  ULN 
 Subject with evidence of acute or chronic infection: Visit 1 or Visit 2 oral temperature 
> 38 °C, a chronic persistent or recurring infection requiring active treatment with 
antibiotics, antivirals or antifungals within 4 weeks prior to the screening visit, or other 
frequent recurrent infections as per investigator judgment. 
 Subject with any contraindications or warning/precaution of use related to MFNS as 
described in the Summary of Product Characteristics. 
3.2.4 Concomitant medications 
Use of concomitant medications must be recorded on the relevant forms of the electronic 
Case Report Form (eCRF). 
3.2.4.1 Mandatory medications 
 MFNS from screening to EOS as standard background therapy. 
 Mandatory therapy includes any treatments required for contraception purposes in 
women of childbearing potential. 
3.2.4.2 Allowed medications 
 Nasal normal saline. 
 Topical decongestants, e.g., oxymetazoline (to reduce the swelling and widen the path 
for the endoscope), and topical anesthetics, e.g., lidocaine, are only allowed before 
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 Lipoxygenase inhibitors and leukotriene antagonists/modifiers unless subject is on 
continuous leukotriene antagonist / modifier treatment for at least 30 days prior to 
screening.  
 Any immunosupressive treatment including but not limited to methotrexate, 
cyclosporine, mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, 
hydroxychloroquine, azathioprine, cyclophosphamide. 
 Anti-IgE therapy.  
 Monoclonal antibody therapy. 
 Acetylsalicylic acid or nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects 
with hypersensitivity to acetylsalicylic acid or NSAIDs. 
# prohibited from Day 1 to EOS. 
3.2.5 Dietary aspects, alcohol, smoking, physical activities 
There are no restrictions in terms of dietary aspects, alcohol, smoking, or physical 
activities.  
ACT-774312 can be administered with or without food. For Visit 3, Visit 4, Visit 5, and 
Visit 6, subjects should arrive fasted at site in the morning without having taken the study 
treatment to collect trough PK samples. 
3.3 Study treatments 
Subjects will take either ACT-774312 or matching placebo. 
Subjects will be instructed to start taking the study treatment on the evening of the 
randomization visit (Visit 2). Thereafter, the subject should take each study treatment dose 
in the morning and evening irrespective of food intake with approximately 12 hours 
between dosings. It is preferable that the study treatment is taken each day (morning and 
evening) at approximately the same time and at the same time as the standard background 
therapy (non-IMP: MFNS 
] 50 μg/actuation nasal spray, suspension; dosing 
regimen: 2 actuations [50 μg/actuation] in each nostril b.i.d. or o.d. if b.i.d. is not tolerated). 
Subjects will be instructed not to take study treatment in the morning of study visit days. 
On the day of the study visits, study treatment must be administered only after completion 
of the pre-dose assessments as indicated in Table 1. 
If a dose is missed, it should be taken as soon as possible. However, the missed dose should 
be skipped if it is almost time for the next dose. To ensure compliance, the study personnel 
must remind subjects at each visit of the study treatment intake requirements. The 
reminders must be documented in the hospital chart.  




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The randomization code will be generated using SAS® software Version 9.4 or newer. No 
stratification factors will be employed in the randomization. 
The randomization list (including code-break envelopes) must be provided to Idorsia 
Pharmaceutical Development Department and the study site prior to the IMP shipment 
release (for more details on blinding/unblinding, see Sections 3.5.4 and 3.5.5). 
The randomization code must be kept strictly confidential and must be accessible only to 
authorized persons who are not involved in the conduct and analysis of the study, until the 
time of unblinding. A sealed randomization code is to be kept by Idorsia Pharmaceutical 
Development Department in a safe cabinet.  
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Idorsia Global Drug Safety will request the unblinding of the 
study treatment assignment. Unblinded SUSAR information will be provided to Idorsia 
Global Drug Safety, respective health authorities, and Independent Ethics Committee / 
Institutional Review Board (IEC/IRB) only. SUSARs will be reported to investigators in 
an unblinded fashion by Idorsia (for more details on blinding/unblinding, see Sections 3.5.4 
and 3.5.5). 
The 
randomization 
code 
will 
be 
released 
to 
the 
bioanalytical 
laboratory 
(Idorsia Pharmaceuticals Ltd, Preclinical Pharmacokinetics and Metabolism, Allschwil, 
Switzerland) in accordance with internal procedures. Provisions will be in place to maintain 
the blinding of sponsor personnel. 
At least 24 subjects will be randomized in a 2:1 ratio as follows: 
 16 subjects will receive ACT-774312 400 mg b.i.d. 
 8 subjects will receive the matching placebo. 
3.5.2 Treatment assignment 
At the randomization visit (Visit 2), and after having verified that the subject meets all 
inclusion criteria and none of the exclusion criteria, the investigator/delegate will assign a 
three-digit number to the subjects in the order of their inclusion in the study before the 
following baseline assessments are performed: 
 CT scan 
 VAS score 
 UPSIT 
 SNOT-22 
 Patient global impression of disease severity 




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time of unblinding. Sealed randomization codes will be kept by the Idorsia Pharmaceutical 
Development Department in a safe cabinet.  
The randomization code will be released to the bioanalytical laboratory (Idorsia 
Pharmaceuticals Ltd, Preclinical Pharmacokinetics and Metabolism, Allschwil, 
Switzerland) prior to database closure and unblinding, in accordance with internal 
procedures. Provisions will be in place to maintain the blinding of sponsor personnel. 
3.5.5 Emergency procedure for unblinding 
The investigator, study staff, and sponsor staff must remain blinded to the subject’s study 
treatment assignment. The identity of the study treatment may be revealed only if the 
subject experiences a medical event, the management of which would require knowledge 
of the blinded treatment assignment. In this case, the investigator can receive the unblinded 
randomization code for study treatment allocation from the emergency code-break 
envelope. In these situations, the decision to unblind resides solely with the investigator. 
Whenever it is possible and if it does not interfere with (or does not delay) any decision in 
the best interest of the subject, the investigator is invited to discuss the intended code break 
with Idorsia. 
The occurrence of any code break during the study must be clearly justified and explained 
by the investigator. In all cases, Idorsia must be informed as soon as possible before or 
after the code break. The circumstances leading to unblinding must be documented in the 
hospital charts and the Investigator Site File (ISF). 
At each monitoring visit, the monitor must check the code-break envelopes. At the end of 
the study, the monitor must collect all code-break envelopes and code-break reports and 
return them to the sponsor for filing.  
3.5.6 Study treatment administration 
The subjects will receive sufficient study treatment to cover the following periods: 
 From Day 1 (Visit 2) to Visit 4. 
 Visit 4 to Visit 5. 
 Visit 5 to Visit 6 (EOT). 
Subjects will be instructed to store the study treatment at room temperature, protected from 
light and moisture. They will be asked to return all used, partially used, and unused study 
treatment bottles at each visit. Should the treatment bottle dispensed at a scheduled visit be 
lost or damaged, a replacement bottle can be requested. 
The protocol-mandated study treatment dispensing procedures may not be altered without 
prior written approval from the sponsor. In exceptional circumstances (e.g., if the subject 


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lost the study treatment between two visits, or if the subject is unable to return to the site 
due to a medical emergency / hospitalization at another hospital), unscheduled dispensing 
and delivery of study treatment may occur outside of a scheduled visit. An accurate study 
treatment record of the date and amount of study treatment dispensed to each subject must 
be available at the site for inspection at any time. 
The inventory of study treatment dispensed to and returned by the subject (i.e., study 
treatment accountability) must be performed by site personnel on the day of the visit and 
before dispensing further study treatment. The Study Treatment Dispensing and 
Administration Log(s) for ACT-774312 and placebo must be kept current by the 
investigator or his/her designee, and must contain as a minimum the following information: 
 Subject number to whom the study treatment was dispensed. 
 Initials and date of the person who dispensed the study treatment. 
 Dispensed bottle ID number. 
 Date dispensed / number of capsules dispensed (recorded in eCRF). 
 Date returned / number of capsules returned (recorded in the eCRF). 
All study treatment supplies, including partially used or empty bottles must be retained at 
the site until they are verified by the unblinded monitor. 
If the subject omits to bring the remaining study treatment to a study visit, he/she must be 
instructed not to take any capsules from the remaining study treatment bottle and to return 
it at the next visit. At Visit 4 and Visit 5, study treatment will be taken from the newly 
dispensed bottles. 
The Study Treatment Dispensing and Administration Log(s) will be collected upon 
completion of the study for archiving in the Trial Master File (TMF). 
3.5.7 Storage and return of study treatment 
The pharmacist is responsible for safe and proper handling and storage of the study 
treatment at the study site in an appropriate lockable room at room temperature (below 
25 °C but not refrigerated). The study treatment should be protected from light. Only the 
pharmacist or his/her designee, who are otherwise not involved in the study, may handle 
the study treatment. 
Upon receipt of the study treatment, the responsible pharmacist or his/her designee must 
inspect and count all study treatment for completeness. Subsequently, he/she must 
immediately return the enclosed acknowledgement of receipt form, duly completed and 
signed (the date of receipt must be noted). 


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The supplies and inventory must be available for inspection by the monitor. The Treatment 
Accountability Log(s) will be collected upon completion of the study for archiving in the 
TMF. 
All unused investigational material (medication and packaging) must be returned to the 
sponsor on termination of the study after a study treatment accountability check by the 
monitor, listing the following: 
 All administered capsules. 
 All unused capsules. 
 All capsules returned at the end of the study, and the date of return. 
The pharmacist will be responsible for the inventory and accountability of all clinical 
supplies, exercising accepted pharmaceutical practices. An accurate, timely record of the 
clinical study supply must be maintained. Only after completion of the study (to avoid 
breaking the blind), will the supplies and the inventory be available for inspection by the 
designated representative(s) of Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland, upon 
request. These records will, however, be made available to the unblinded monitor if needed.  
Once the clinical study report has been finalized, the study treatment will be destroyed by 
the site if possible. If not, the IMP has to be sent back to Idorsia Pharmaceuticals Ltd, 
Allschwil, Switzerland, for destruction. 
3.5.8 Study treatment dosing scheme 
Table 4 
Dosing scheme 
Study period 
Duration 
Study treatments 
Dose  
regimen  
Standard background 
therapy (dose regimen) 
Run-in 
Day 30 to Day 1 
4 weeks 
– 
– 
MFNS (100 μg in each 
nostril b.i.d. or o.d.) 
Treatment 
Day 1 to EOT 
12 weeks 
Placebo or 
ACT-774312 
400 mg b.i.d. 
MFNS (100 μg in each 
nostril b.i.d. or o.d.) 
Post treatment 
EOT to EOS 
30 days 
– 
– 
MFNS (100 μg in each 
nostril b.i.d. or o.d.) 
b.i.d. = twice daily; EOS = End-of-Study; EOT = End-of-Treatment; MFNS = mometasone furoate nasal spray; o.d. = 
once daily. 
 
3.5.9 Study treatment up- and down-titration 
Not applicable. 


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3.6 Study treatment discontinuation and study discontinuation 
3.6.1 Study treatment dose adjustment  
Study treatment dose adjustment is prohibited. 
3.6.2 Study treatment interruption or discontinuation 
The investigator must temporarily interrupt or permanently discontinue the study treatment 
if he or she believes continued administration of the study treatment to be contrary to the 
best interests of the subject. Interruptions of study treatment must be kept as short as 
possible. 
The interruption or premature discontinuation of study treatment might be triggered by an 
AE, a diagnostic or therapeutic procedure, an abnormal assessment (e.g., laboratory 
abnormalities), or for administrative reasons – in particular, withdrawal of the subject’s 
consent.  
A subject has the right to prematurely discontinue study treatment at any time, without any 
justification, by withdrawing from study treatment only or by withdrawing from any further 
participation in the study (i.e., premature withdrawal from the study). Although a subject 
is not obliged to give his/her reason for prematurely withdrawing from the treatment or the 
study, it is recommended that the investigator makes a reasonable effort to ascertain the 
reason(s), while fully respecting the subject’s rights. 
A subject who prematurely discontinues study treatment is not considered as withdrawn 
from the study and will be followed in the post-treatment period, provided that the subject’s 
consent for this participation in the study has not been withdrawn.  
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 
Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study are described in Sections 3.6.5 and 3.6.6, respectively. 
The date and the reason for study treatment interruption or premature discontinuation must 
be documented in the eCRF and the sponsor must be informed. If the reason for study 
treatment interruption or premature discontinuation from study treatment is an abnormal 
result on laboratory test, vital sign, ECG recording, or physical examination, this 
information must be recorded as an AE in the eCRF. The EOS assessments must be 
performed as planned 30 (+2 days) after the last study treatment administration. Study 
treatment may be temporarily interrupted in response to an AE (maximum 2 weeks of 
interruption), or other reasons (e.g., diagnostic or therapeutic procedure, study treatment 
forgotten). 


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If study treatment is interrupted by the subject for any reason, he/she must immediately 
inform the investigator. 
All study treatment interruptions must be recorded in the eCRF. 
If the number of subjects who prematurely discontinue study treatment is higher than 
expected, additional subjects may be randomized, see Section 3.5.3. 
3.6.3 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
Pregnancy 
If a subject becomes pregnant while on study treatment, study treatment must be 
permanently discontinued. The investigator/delegate must counsel the subject and discuss 
the risks of continuing with the pregnancy and the possible effects on the fetus. 
Vital signs 
If a subject experiences SBP < 80 mmHg and DBP < 60 mmHg (confirmed by repeated 
BP measurement within 10 min) and associated with significant clinical symptoms while 
on investigational treatment, study treatment must be permanently discontinued.  
Severe thrombopenia 
If a subject experiences a severe thrombopenia (platelets count < 50,000/μL) while on 
investigational treatment, study treatment must be permanently discontinued. 
3.6.4 Subject’s follow-up after study treatment discontinuation 
A subject who prematurely discontinues study treatment will be followed in the 
post-treatment period.  
3.6.5 Study discontinuation 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost to 
follow-up. If a subject withdraws consent, no further data will be collected in the eCRF 
from the date of withdrawal onward. The investigator may withdraw a subject from the 
study (without regard to the subject’s consent) if, 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 fail. The site must take preventive measures to avoid a 


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subject being lost to follow-up (e.g., document different ways of contact such as telephone 
number, home address, e-mail 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 and document all attempts and follow-up information on source. The following 
methods must be used: at least three telephone calls must be placed to the last available 
telephone number and one registered letter must be sent by post to the last available home 
address. Additional methods may be acceptable if they are compliant with local 
rules/regulations (e.g., site staff visit 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.  
The date and the reasons for premature discontinuation of the study must be documented 
in the eCRF, and the sponsor must be informed. 
3.6.6 Subject follow-up after study discontinuation 
If for whatever reason (except death or loss-to-follow-up) a subject is withdrawn from the 
study, the investigator should make best efforts to schedule a last appointment / telephone 
call to assess the safety and well-being of the subject, collect unused study treatment, and 
discuss follow-up medical care. Data obtained during this last appointment / telephone call 
will be recorded in the subjects’ medical records but it will not be collected in the eCRF. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
Subjects who discontinue the study may request that all biological samples drawn in the 
course of the study be destroyed. 
3.6.7 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local regulations.  
Female subjects of childbearing potential will be reminded of the contraception 
requirements as described in Section 3.2.2. 
3.7 Study treatment exposure and compliance 
Records of study treatment used, dosages administered, and intervals between visits are to 
be kept during the study. Study treatment accountability is to be performed on an ongoing 
basis by the study staff, and checked by the monitor during site visits and at completion of 
the study.  
Study treatment compliance will be assessed based on the difference between the number 
of capsules provided to the subject and the number of capsules brought back at each 


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dispensing visit. In the event of loss of study treatment, the Subject Diary will be used to 
calculate compliance. 
Study treatment compliance with the prescribed study treatment dose regimen will be 
confirmed by the sponsor based on Subject Diary data. On each day, subjects will be asked 
to enter in the Subject Diary the number of capsules taken in the morning and evening as 
well as the dosing time. 
For each time interval between two visits, study treatment compliance will be calculated 
by the sponsor using the following formula: 
Study treatment compliance = Number of capsules taken during the period / Total number 
of times the study treatment should have been taken during the period  100 
The prescribed dose corresponds to 400 mg ACT-774312 / placebo. The period is defined 
as the number of days between visit n (or date of first study treatment intake if 
randomization visit) and visit n+1 (or date of last study treatment intake if EOT visit). 
The number of times the study treatment should have been taken at the prescribed dose 
regimen in each period is calculated as follows: 
 (Number of days in the period – 1) 2 + 1 for the first period and the last period as 
only 1 administration will take place on Day 1 and on EOT 
 Number of days in the period 2 for the period Visit 4 to Visit 5 
Study treatment interruption(s) will be ignored when calculating study treatment 
compliance. 
Between visits, study treatment compliance is expected to be at least 80%. The sponsor 
will inform the site staff and monitor about any compliance values below 80%. Compliance 
values below 80% without medical justification (e.g., AE) and not related to a Subject 
Diary completion issue will be considered as a protocol deviation, which will be reported 
as such to the sponsor by the monitor. In such cases, the investigator must discuss and 
clarify the reasons for non-compliance with the subject and take appropriate actions to 
avoid re-occurrence. 
The measurement of plasma levels of ACT-774312 in the analytical phase will serve as a 
further check of compliance. 
3.8 Study endpoints 
3.8.1 Efficacy endpoints 
Baseline: Defined as the last value measured prior to first intake of study treatment. 




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 Treatment-emergent# ECG abnormalities at EOT.  
 Change from baseline to Weeks 2, 4, 8, 12, and EOS in clinical laboratory tests.  
 Treatment-emergent AEs up to EOS. 
 Treatment-emergent SAEs up to EOS. 
 AEs leading to premature discontinuation of study treatment up to EOT. 
 Treatment discontinuation due to systemic corticosteroid administration for NP and/or 
surgery for nasal polyps before Week 12. 
# Treatment-emergent is defined from first study treatment administration up to EOS. 
3.8.2.1 Safety and tolerability endpoints  derived variables 
QTcF will be derived using the ECG variables QT and HR (for calculation of RR) recorded 
in the eCRF. 
 QTcF (ms) = QT (ms)/RR (s) 0.33 where RR is 60/HR (bpm) 
3.8.3 Pharmacokinetic and pharmacodynamic endpoints 
The plasma PK parameters of ACT-774312 at Week 2 will be derived by 
noncompartmental analysis of the plasma concentration-time profile.  
3.8.3.1 Pharmacokinetic endpoints 
 Trough ACT-774312 concentration at Weeks 2, 4, 8, and 12. 
 AUC from zero to 4 h (AUC at Week 2. 
 AUC over a dosing interval (AUC at Week 2 by extrapolation of the 12 h trough 
concentration based on the pre-dose trough concentration. 
 Cmax at Week 2. 
 tmax at Week 2. 
3.8.3.2 Calculation of pharmacokinetic endpoints and assumptions 
The measured individual plasma concentrations of ACT-774312 will be used to directly 
obtain Cmax and tmax. 
AUC04 will be calculated according to the linear trapezoidal rule using the measured 
concentration-time values above the limit of quantification (LOQ). AUCτ will be 
extrapolated from AUC04 by using the pre-dose concentration as well as the trough 
concentration at 12 h.  
The PK parameters will be calculated on the basis of the actual blood sampling time points.  




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Table 5 
Endoscopic nasal polyp score 
Polyp score 
Polyp size 
0 
No polyps 
1 
Small polyps in the middle meatus not reaching below the inferior 
border of the middle turbinate 
2 
Polyps reaching below the lower border of the middle turbinate 
3 
Large polyps reaching the lower border of the inferior turbinate or 
additional large polyps medial to the middle turbinate 
4 
Large polyps causing near-complete obstruction of the inferior nasal 
cavity, i.e., touch the floor of the nose 
 
The results of both the local and central assessments of the NPS will be reported in the 
eCRF. 
Further details on nasal endoscopy will be available in a separate operational manual 
provided to the site. 
3.9.1.2 CT scan 
CT of the sinuses should be performed at Visit 2 and at EOT (Visit 6). 
For Lund-Mackay score, Zinreich-modified Lund-Mackay score, and 3D volumetric 
measurement of the maxillary sinus, the same acquisitions (sequences) will be used for 
centralized imaging data assessments and scoring by independent physician reviewers for 
the imaging data. The subject-identifying information (subject and visit identifiers) will be 
removed by ERT prior to sending the data to the reader. The final results of central reading 
will be made available after EOS.  
Local assessment of the Lund-Mackay score will also be performed. 
Details on CT will be available in a separate operational manual provided to the site. 
The Lund-Mackay and the Zinreich-modified Lund-Mackay systems are based on 
localization, with points given for degree of opacification. 
Lund-Mackay score 
The right or left sinuses are divided into six portions, i.e., maxillary sinus, anterior ethmoid 
sinuses, posterior ethmoid sinuses, sphenoid sinus, frontal sinus, and OMC. The score 
assignments are 0 if the sinus is totally patent, 1 if the sinus is partially opacified, and 2 if 


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the sinus is completely opacified. The maximum score for each side is thus 12, with a total 
score determined out of 24. The OMC is scored either 0 if not occluded or 2 if occluded. 
Modification of the Lund-Mackay score 
Each sinus is assigned a score based on the percentage of opacification from mucosal 
thickening as follows: 0 = 0%, 1 = 1% to 24%, 2 = 25% to 74%, 3 = 75% to 99%, 4 = 100% 
or completely occluded. Similar to the Lund-Mackay system, each side is graded and their 
sum is the total score out of a maximum of 48. The OMC is given a score of 0 (no 
obstruction) or 1 (obstruction) for the frontal recess, middle meatus, infundibulum, and the 
sphenoethmoidal recess channels. 
For subjects in whom the OMC is missing (because of a previous surgery) the reader should 
consider the location of the former OMC and provide a scoring (as if the OMC was there). 
3D volumetric measurement of the maxillary sinus (left and right) 
This method is used to calculate:  
 the volume of air (mL) 
 the volume of mucosa (mL) 
 % occupied by disease 
 thickness of lateral wall 
The subject-identifying information from the imaging data header will be removed by ERT 
prior to sending the imaging data to the physician for reading.  
Both the Lund-Mackay score and the 3D volumetric measurements of the maxillary sinus 
will be reported in the eCRF. 
3.9.1.3 UPSIT 
UPSIT should be performed at all visits except Visit 1. 
The UPSIT test is a rapid and easy-to-administer method to quantitatively assess human 
olfactory function [Doty 1984]. The UPSIT shows a high test-retest reliability (r: 0.981) 
and scores on this test are strongly correlated with the detection threshold for 
phenylethylalcohol in the same individuals. When the UPSIT is administered in the 
standardized manner, clinical subjects show a high degree of uniformity in UPSIT 
performance when tested in different laboratories. 
The test consists of four booklets, each containing 10 odorants with one odorant per page. 
The test-time is about 15 min. The stimuli are embedded in 1050 (m) diameter plastic 
microcapsules on brown strips at the bottom of each page. Above each odorant strip is a 
multiple-choice question with four alternative words to describe the odor. The subject will 


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be asked to release the odorant by rubbing the brown-strip with the tip of a pencil and to 
indicate which of four words best describes the odor. Each subject will receive a score out 
of 40 possible correct answers. The final score will be recorded in the eCRF. 
3.9.1.4 Visual analog scales for symptoms  
The patient will be asked to indicate on a VAS the answer to the question: “How 
troublesome are your symptoms?” for the 5 following symptoms: 
 nasal obstruction 
 nasal discharge 
 mucus in the throat 
 loss of smell 
 facial pain 
Each symptom will be assessed individually based on total severity of the VAS score (0 to 
10 cm). The VAS ranks from 0 (Not at all troublesome) to 10 (Extremely troublesome) 
The scores for the 5 symptoms will be added together and the total score will be categorized 
as MILD, MODERATE, or SEVERE, where:  
MILD = VAS 015 
MODERATE = VAS > 1535 
SEVERE = VAS > 3550 
The total score will be recorded in the eCRF. 
A sample of the VAS for each symptom is provided 
. 
3.9.1.5 Physician Global Assessment  
 PGA-DS 
The questionnaire will be completed by the physician at Visit 2 and at each subsequent 
site visit until EOS. The questionnaire will be administered in a paper format. 
The physician will rate the overall severity of the disease symptoms on a 4-point scale 
(1–4) scored as: “none”, “mild”, “moderate”, or “severe”. 
A sample of the PGA-DS questionnaire is provided 
. 
 PGA of Change in Disease Severity (PGAC-DS) 


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The questionnaire will be completed by the physician at Week 2 (Visit 3), and at each 
subsequent site visit until EOS. The questionnaire will be administered in a paper 
format. 
The PGAC-DS questionnaire is a self-administered 1-item questionnaire designed to 
assess the physician’s impression of change in disease severity since study treatment 
start. The physician will rate the change since the subject started study treatment in the 
overall severity of the disease symptoms on 7-point scales (1 to 7) scored as: “very 
much improved,” “much improved,” “minimally improved,” “no change,” “minimally 
worse,” “much worse,” or “very much worse”. 
A sample of the PGAC-DS is provided
. 
The answers to the 2 questionnaires will be recorded in the eCRF. 
3.9.1.6 Patient questionnaires 
 SNOT-22 
The SNOT-22 is a validated questionnaire to assess the impact of CRS on QoL. 
The score ranges from 0 to 110. Higher total scores on the SNOT-22 imply greater 
impact on QoL. The SNOT-22 was validated and recommended for routine clinical 
practice. A minimal clinically important difference in score has been established to be 
8.9 points [Hopkins 2009]. 
The score will be reported in the eCRF. 
The sponsor has obtained approval from the developer of the SNOT-22 for its use in 
this study. Validated translation for Flemish has been obtained 
A sample of the SNOT-22 questionnaire is provided for each symptom 
. 
 Patient Global Impression of Change in Disease Severity (PGIC-DS) 
A PGIC-DS questionnaire will be completed by the subject at Week 2 (Visit 3) and at 
each subsequent site visit until EOS. The questionnaire will be administered in a paper 
format. 
The PGIC-DS questionnaire is a self-administered 1-item questionnaire designed to 
assess subject’s impression of change in disease severity since study treatment start. 
Subjects will rate their change since they started study treatment in the overall severity 
of the disease symptoms on 7-point scales (1 to 7) scored as: “very much improved,” 
“much improved,” “minimally improved,” “no change,” “minimally worse,” “much 
worse,” or “very much worse”. 


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The answer to the questionnaire will be recorded in the eCRF. 
A sample of the PGIC-DS questionnaire is provided 
. 
3.9.2 Safety and tolerability assessments 
The definitions, reporting, and follow-up of AEs, SAEs, and potential pregnancies are 
described in Section 4. 
See Table 1 for the time points of assessments. 
3.9.2.1 Specific safety and tolerability assessments 
3.9.2.1.1 Weight and height 
Height will be measured in cm at screening only. Body weight will be measured in kg at 
screening and the EOS visit. The results should be provided to one decimal place and the 
values, as well as the BMI, will be recorded in the eCRF. 
The subjects’ body weight will be measured using the same weighing scale for all subjects 
and throughout the study. The weighing scale should have a precision of at least 0.5 kg. 
3.9.2.1.2 Physical examination 
Physical examination (i.e., inspection, percussion, palpation, and auscultation) will be 
performed at Visits 1, 2, 6, and 7. Clinically relevant findings found after informed consent 
form (ICF) signature and meeting the definition of an AE (new AE, or worsening of 
previously existing condition) must be recorded on an AE form of the eCRF. 
Date and time of physical examination and its results will be recorded on source documents 
only. 
3.9.2.1.3 Vital signs 
SBP, DBP and pulse rate will be measured at all visits using an automatic oscillometric 
device, always on the dominant (i.e., dominant arm right = writing with right hand).  
In this study the normal range for vital signs is defined as follows:  
SBP:  
100160 mmHg 
DBP:  
50100 mmHg 
Pulse rate: 
45100 bpm 
Measurements should be recorded from the subject in the supine position after having 
rested for a 5-minute period. The date and time of the vital sign measurements and the 
corresponding results will be recorded in the eCRF. 


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Significant findings made after study treatment initiation which meet the definition of an 
AE must be recorded on an AE form of the eCRF. 
If felt necessary by the investigator, additional vital signs may be recorded to substantiate 
abnormal findings on the vital signs, which will be also recorded in the eCRF. 
3.9.2.1.4 Electrocardiography 
A standard 12-lead ECG is to be recorded at rest with the subject in the supine position for 
a 5-minute period. Printouts for each ECG (at least three complexes for each standard lead) 
will include date and time of recording, subject’s identification, physician’s evaluation, and 
physician’s initials. The date and time of the ECG recordings as well as the overall ECG 
evaluation and potential abnormal findings of the ECG recordings will be transcribed into 
the subject’s eCRF. 
The following variables are to be collected on the eCRF: PR (ms), QRS (ms), QT (ms), 
QTcB (ms), HR (bpm), and RR.  
If felt necessary by the investigator, additional ECGs may be recorded to substantiate 
abnormal findings on the ECG, which will be also recorded in the eCRF. 
Significant findings made after study treatment initiation, which meet the definition of an 
AE, must be recorded on an AE form of the eCRF. 
3.9.2.2 Laboratory assessments 
3.9.2.2.1 Type of laboratory 
For each laboratory, the investigator must provide the sponsor with the name and 
professional degree, a copy of the laboratory’s certification, and the normal range (by sex, 
if appropriate) for each variable being evaluated in the study. These laboratory references 
must be forwarded to the sponsor before study start, and be updated whenever necessary. 
However, the investigator must request that the clinical laboratory does not change any 
normal range during the course of the study. 
If a sample is lost or cannot be analyzed by the laboratory the sample will not be 
re-collected.  
For each assessment of routine laboratory variables, a total of 18 mL of blood will be taken 
from each subject (9 mL for hematology and 9 mL for clinical chemistry). Urinalysis will 
be performed by dipstick. 
Virus serology and IgE titer will be measured at screening only; a total of 18 mL of blood 
will be taken from each subject.  


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A serum pregnancy test will be performed at screening (4 mL of blood) in women of 
childbearing potential, and a urine pregnancy test will be performed at Visit 2 prior to 
randomization. A negative result must be obtained at Visits 1 and 2 prior to randomization. 
Additional urine pregnancy tests will be performed at each visit until EOS visit. 
For cyp2c9 genotyping, a total of 4 mL of blood will be taken from each subject at 
screening. 
The blood samples will be taken under fasted conditions. As a rule, the blood samples will 
be taken from the subject in the sitting position by puncture of a vein in the cubital or the 
antebrachial region. The samples will be sent to the local certified laboratory immediately 
after blood sampling. The date and time of the blood sampling will be recorded in the 
eCRF. 
If subjects present with abnormal laboratory test results during the study, additional 
re-checks and monitoring will be performed as applicable. 
All abnormal laboratory values must be assessed by the investigator and marked as 
clinically significant (CS) or not clinically significant (NCS) on the laboratory printout and 
in the eCRF. Clinically significant laboratory abnormalities observed after study treatment 
administration, which meet the definition of an AE, must be reported by the investigator 
as an AE or SAE as appropriate [see Section 4]. 
The results from virus serology, urinalysis, and pregnancy test will be documented on a 
separate source document and entered in the eCRF. 
3.9.2.2.2 Laboratory variables 
Hematology 
 Hemoglobin, hematocrit 
 Red blood cell count 
 White blood cell count 
 Differential blood count (including: basophils, eosinophils, neutrophils, lymphocytes, 
monocytes) 
 Platelet count 
Clinical chemistry 
 Urea 
 Creatinine 
 Total bilirubin 
 Direct bilirubin 
 Alkaline phosphatase 
 Aminotransferases (AST/ALT) 


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 Creatine phosphokinase 
 Gamma glutamyl transferase 
 Lactate dehydrogenase 
 Uric acid 
 Glucose 
 Cholesterol, triglycerides 
 Sodium, potassium, chloride, calcium 
 Protein, albumin 
Pregnancy test 
At screening, a human chorionic gonadotropin (hCG) serum pregnancy test will be 
performed by automated immunoassay using the clinical chemistry blood sample. At all 
other time points, pregnancy testing will be performed in urine using a qualitative 
chromatographic immunoassay hCG kit. 
Urinalysis 
 Glucose 
 Bilirubin 
 Ketone 
 Specific gravity 
 Blood 
 pH 
 Protein 
 Urobilinogen 
 Nitrite 
 Leukocytes 
 Microscopic urine analysis if dipstick positive (in the event of out of range data) 
Virus serology 
 HIV1 and HIV2 antibodies 
 Hepatitis B antigen and hepatitis C antibodies 
Virus serology will be measured at the screening visit. 
FSH (females of non-childbearing potential only) 
At screening, FSH will be measured to confirm the post-menopausal status of women of 
non-childbearing potential if necessary. 








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3.9.4.4 Previous and concomitant medications 
A previous medication is any treatment for which the end date is prior to the first study 
drug administration.  
All medication that is study-concomitant (i.e., ongoing or initiated after first study drug 
administration) must be captured in the eCRF.  
Previous/concomitant medications (including contraceptives and traditional and alternative 
medicines, i.e., plant-, animal-, or mineral-based medicines) from 3 months prior to 
screening, or started during the course of the study, until EOS must be recorded in the 
eCRF. The generic name, start/end dates of administration (as well as whether it was 
ongoing at start of treatment), route, dose, and indication will be recorded in the eCRF. 
3.9.4.5 Immunoglobulin E titer 
Total IgE will be measured at Visit 1 and will be recorded in the eCRF. 
3.9.4.6 Spirometry 
Spirometry test will be performed at Visit 1 for subjects with asthma as based on their 
medical history. The following must be avoided for the duration shown prior to spirometry 
testing: caffeine-containing drinks (1 hour), alcoholic beverages (4 hours), strenuous 
exercise (30 minutes), and large meals (2 hours). Cold air should also be avoided 
immediately prior to testing. 
Testing should be started after the patient has rested for at least 5 minutes. Testing will be 
conducted with the patient seated and wearing nose-clips. Subjects should be given clear 
instructions before and during the testing, and should be actively coached and encouraged 
during the test. When performing the test, subjects should remain erect and not bend 
forward excessively.  
The FEV1 value will be recorded in the eCRF. 
3.9.4.7 Asthma Control Questionnaire 
The Asthma Control Questionnaire (ACQ) will be completed by subjects with asthma 
(based on medical history) only. The ACQ is a self-administered tool that measures the 
adequacy of asthma control and the change in asthma control which occurs either 
spontaneously or because of a treatment [Juniper 1999]. The ACQ has seven questions, the 
first five of which score the asthma symptoms, and the last two of which score the daily 
reliever bronchodilator use during the previous week and the FEV1% predicted on the day 
of the assessment. In the ACQ, subjects are asked to recall how their asthma has been 
during the previous week, and to respond to the symptom and bronchodilator use questions 
on a 7-point scale (0 = no impairment, 6 = maximum impairment). Clinic staff score the 
FEV1% predicted on a 7-point scale. The questions are equally weighted and the ACQ 


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score is the mean of the seven questions; ACQ scores may therefore vary between 0 and 6. 
The ACQ will be self-administered at Visit 1 only, and only by the subjects with asthma. 
The responses to the ACQ questions are collected in the eCRF. 
A sample of the ACQ (in English) is provided 
. 
The sponsor has obtained approval from the developer of the ACQ for its use in this study. 
Validated translations for Flemish have been obtained. 
3.9.4.8 Asthma Quality of Life Questionnaire 
The Asthma Quality of Life Questionnaire with Standardised Activities (AQLQ) will be 
completed by subjects with asthma (based on medical history) only. The AQLQ was 
developed and validated to measure the functional problems (physical, emotional, social, 
and occupational) that are most troublesome to adults (17–70 years) with asthma 
[Juniper 1992]. This instrument has 32 questions in four domains (symptoms, activities, 
emotions, and environment) and takes 3–4 minutes to complete. Subjects are asked to think 
about how they have been during the previous 2 weeks and to respond to each of the 
32 questions on a 7-point scale (7 = not impaired at all to 1 = severely impaired). The 
overall AQLQ score is the mean of all 32 responses, and the individual domain scores are 
the means of the items in those domains. The responses to the AQLQ questions are 
collected in the eCRF. The AQLQ will be assessed at Visit 1 only, and only for the subjects 
with asthma. 
A sample of the AQLQ (in English) is provided 
. 
The sponsor has obtained approval from the developer of the AQLQ for its use in this 
study. A validated translation for Flemish has been obtained. 
3.10 Visit and assessment schedule 
Table 1 provides an overview of the assessments during the study. 
3.10.1 Sequence of assessments 
All assessments must be scheduled in such a way that the time point of PK sampling is 
strictly kept ± 5% (in relation to the last study treatment intake). 
Nasal secretion samples should be collected before the endoscopy. 


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3.10.2 Total blood volume 
The total volume of blood to be taken per subject during the entire course of the study will 
be as follows: 
Table 6 
Example of total blood volume taken at the coordinating site 
Procedure 
Sample 
Blood 
volume per 
sample (mL) 
Number of 
blood samples 
per subject 
Total volume 
per subject 
(mL) 
Laboratory tests 
Hematology 
9 
7 
63 
Biochemistry incl. glucose 
9 
7 
63 
Serology and IgE titer 
18 
1 
18 
Pregnancy serum test 
4 
1 
4 
cyp2c9 genotyping 
4 
1 
4 
Bioanalysis 
 
 
 
 
 
 
 
 
Total volume of blood collected 
212 
IgE = immunoglobulin E; PD = pharmacodynamics; PK = pharmacokinetics. 
 
Overall, including potential additional safety laboratory assessments, the total volume of 
blood will not exceed 250 mL over 5 months at any of the sites. This volume is lower than 
the volume of blood collected during a blood donation. 
4 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
4.1 Adverse events 
4.1.1 Definitions of adverse events 
An AE is any adverse change from the subject’s baseline condition, i.e., any unfavorable 
and unintended sign, including an abnormal laboratory finding, symptom or disease, that 
occurs during the study, whether or not considered related to the study treatment.  
A treatment-emergent AE is any AE temporally associated with the use of a study 
treatment, whether or not considered related to the study treatment.  
AEs include: 
 Exacerbation of a pre-existing disease. 
 Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 


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 Disease or medical condition detected or diagnosed after signature of the ICF even 
though it may have been present prior to the start of the study. 
 Continuous persistent disease or symptoms present at baseline that worsen following 
the first study treatment administration. 
 Abnormal assessments, e.g., ECG, vital signs, or physical examination findings, if they 
represent a clinically significant finding that was not present at baseline or worsened 
during the study. 
 Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at baseline or worsened during the course 
of the study or led to dose reduction, interruption or permanent discontinuation of study 
treatment. 
Overdose, misuse, and abuse of the study treatment should be reported as an AE and, in 
addition, study treatment errors must be documented in the study treatment log of the 
eCRF. 
4.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is to be reported on specific AE forms of the eCRF.  
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity is to be reported on the AE page. If the AE lessens in intensity, no change in the 
severity is required. 
If an AE occurs during a washout or placebo run-in phase and afterwards worsens during 
the treatment phase, a new AE form must be filled out with the intensity observed during 
study treatment administration. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not influence daily activities, and 
usually does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
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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 4.3.1]. 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 severity assessment, determines the regulatory reporting 
obligations. 
4.1.3 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 an investigator who is a qualified physician. 
4.1.4 Adverse events related to study design or protocol-mandated procedures  
An AE is defined as related to study design or 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. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of underlying disease. 
4.1.5 Reporting of adverse events 
All AEs with an onset date after signing of the ICF and up to 30 days after study treatment 
discontinuation or up to EOS must be recorded on specific AE forms of the eCRF. 
Information to be collected in an AE form in the eCRF includes date of onset, action taken 
with the study treatment, outcome of AE, date of resolution (if applicable) and 
investigator’s assessment of intensity, and relationship to study treatment, study design or 
protocol-mandated procedures. 
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity should be reported on the AE form. If the AE lessens in intensity, no change in 
the severity is required to be reported. 
For AEs ongoing at the start of study treatment, information on worsening of intensity after 
the start of study treatment will be collected on the AE form. 
Follow-up information on ongoing AE obtained after the subject’s EOS visit will not be 
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4.1.6 Follow-up of adverse events 
AEs still ongoing at EOS for a given subject must be followed up until they are no longer 
considered clinically relevant. The final outcome of AEs that were ongoing at the EOS 
examination will not be recorded in the eCRF (kept in source document only); these events 
will be marked as ongoing in the eCRF. The final outcome of these AEs will be provided 
in the clinical study report. 
4.2 Suspected unexpected serious adverse reactions 
The expectedness of an SAE is determined by the sponsor according to 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. 
4.3 Serious adverse events 
4.3.1 Definitions  
4.3.1.1 Serious adverse events 
An SAE is defined by ICH guidelines as any AE fulfilling at least one of the following 
criteria: 
 Fatal. 
 Life-threatening: refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe. 
 Requiring inpatient hospitalization, or prolongation of existing hospitalization. 
 Resulting in persistent or significant disability or incapacity. 
 Congenital anomaly or birth defect. 
 Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject, and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above.  
The following reasons for hospitalization are exempted from being reported:  
 Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
 Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, e.g., hospitalization for coronary angiography in a subject with stable 
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However, complications that occur during hospitalization are AEs or SAEs (for example if 
a complication prolongs hospitalization). 
4.3.1.2 Serious adverse events associated with the study design or protocol-mandated 
procedures  
An SAE is defined as related to study design or 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. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of underlying disease or a 
complication of an invasive procedure that is specifically required by the protocol. 
4.3.2 Reporting of serious adverse events  
All SAEs occurring after signing of the ICF up to 30 days after study treatment 
discontinuation or up to EOS must be recorded on an SAE form. 
4.3.2.1 After the follow-up period  
New SAEs occurring at any time after the 30-day follow-up period after study treatment 
discontinuation must be reported to the Idorsia Global Drug Safety department within 24 h 
of the investigator’s knowledge of the event, if considered causally related to previous 
exposure to study medication by the investigator. These SAEs are only entered in the drug 
safety database, and hence will not affect study closure. 
4.3.2.2 Reporting procedures 
All SAEs must be reported by the investigator to the Idorsia Global Drug Safety department 
without delay and at the latest 24 h after the investigator’s first knowledge of the event. 
All SAEs must be recorded on SAE forms, 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.  
These SAE forms must be e-mailed to the Idorsia Global Drug Safety department (for 
contact details, see page 3). The investigator must complete the SAE form in English, and 
must assess the causal relationship of the event to study treatment. 
Such preliminary reports must be followed by detailed descriptions that should include 
copies of hospital case reports, autopsy reports, hospital discharge summaries and other 
documents when requested and applicable. Follow-up information about a previously 
reported SAE must also be reported within 24 hours of receiving it. The Idorsia Global 
Drug Safety department may contact the investigator to obtain further information.  
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and 
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4.4.3 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion, and its outcome must be reported to the 
Idorsia Global Drug Safety department. 
Such follow-up information will only be entered in the sponsor’s drug safety database, and 
hence will not affect study closure. 
5 
STATISTICAL METHODOLOGY AND ANALYSES 
5.1 Statistical analysis plan 
A statistical analysis plan (SAP) will be written and finalized before study closure, 
i.e., database closure and unblinding of the randomization code. The SAP will provide full 
details of the analyses, data displays, and algorithms to be used for data derivations.  
The SAP will include the definition of major and minor protocol deviations and the link 
between major protocol deviations and the analysis sets. Major and minor protocol 
deviations will be identified by trained staff before study closure. 
5.2 Analysis sets 
Four analysis sets are defined. 
 All-treated set (ATS) 
This analysis set includes all randomized subjects who received at least one dose of the 
study treatment. 
The ATS will be employed in the analysis of the demographic, baseline, (primary) efficacy, 
and safety variables. 
 Per-protocol set (PPS) 
This analysis set includes all randomized subjects who completed the treatment up to 
Week 12 without protocol deviations that may affect the evaluation of the primary 
endpoints (to be defined in the SAP).  
The PPS will be employed in the analysis of efficacy variables. 
The target number of subjects in the PPS is 21. If this number is unlikely to be reached, the 
number of subjects to be randomized may be increased over 24.  
 Pharmacokinetic set (PK set) 
This analysis set comprises all subjects from the ATS who completed treatment with 
ACT-774312 at least up to Week 2, had evaluable plasma concentrations, and did not 
deviate from the protocol in a way that might affect the evaluation of the PK endpoints. 
The PK set will be employed in the analysis of the PK parameters. 


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 Pharmacodynamic set (PD set) 
This analysis set comprises all subjects from the ATS who completed treatment with 
ACT-774312 or placebo at least up to Week 2 without protocol deviations that may affect 
the evaluation of the PD endpoints.  
The PD set will be employed in the analysis of the PD variables. 
5.3 Primary endpoint 
The primary endpoint is the change from baseline to Week 12 in NPS as measured by nasal 
endoscopy (centrally assessed). 
5.3.1 Statistical model 
The statistical model for the changes from baseline in NPS is a mixed model for repeated 
measurements (MMRM): 
Yijt = µ + αi + βt + (αβ)it + γXij + δtXij+ εijt where  
Yijt is the change from baseline to time t (Week 2, Week 4, Week 8 or Week 12) for 
subject j in treatment group i; 
µ is the overall mean change from baseline; 
αi is the effect of treatment group i (∑αi = 0);  
βt is the effect of time t (∑βt = 0); 
(αβ)it is the interaction of treatment i and time t (∑(αβ)it = 0); 
Xij is the baseline NPS for subject j in treatment group i; 
δt is the interaction of baseline NPS and time (∑δt = 0); 
εijt is an error term where the vector εij follows a multivariate normal distribution with 
mean (vector) 0 and an unstructured covariance matrix ∑. 
Inference for the linear mixed model is based on restricted maximum likelihood estimation 
[Verbeke 2000]. Study site is not shown above but will be added to the model. 
5.3.2 Hypotheses and statistical inference 
Statistical hypotheses will not formally be tested in this estimation study. 
5.3.3 Primary endpoint analysis 
5.3.3.1 Main analysis 
The main analysis of the primary efficacy endpoint will be conducted on the PPS. All NPS 
values observed between baseline and Week 12 will be included in this analysis. 
Changes from baseline to post-baseline visits in NPS will be analyzed using an MMRM 
with factors for treatment group, study site, visit, treatment by visit interaction and 
covariates for baseline NPS and the interaction between baseline NPS and visit. An 


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unstructured covariance matrix will be used to account for the correlation between repeated 
measurements from the same subject. 
Estimation of the treatment difference for the primary endpoint, change from baseline to 
Week 12 in NPS, will be based on the mixed model.  
Missing data handling in the primary analysis 
All subjects in the PPS are expected to have a Week 12 NPS. Any intermediate missing 
data will be handled by the mixed model. Missing values will not be imputed. 
5.3.3.2 Confirmatory analyses 
A sensitivity analysis will be conducted on the ATS using the same mixed model as for the 
primary analysis. In this approach missing values will not be imputed, but will be handled 
by the model assuming that the data are missing at random. Additionally, an analysis of 
covariance (ANCOVA) will be performed for the change from baseline to Week 12 in NPS 
with missing data imputed using last observation carried forward. 
5.3.4 Primary endpoint display 
The primary endpoint will be summarized by visit and treatment group displaying number 
of observations, mean, median, standard deviation (SD), minimum, and maximum. 
5.4 Secondary efficacy endpoints 
All secondary endpoints are listed in Section 3.8.1.  
5.4.1 Secondary efficacy endpoint analysis 
Secondary efficacy endpoints will be analyzed in the PPS. Change from baseline to 
Week 12 in Zinreich-modified Lund-Mackay score will be analyzed using an ANCOVA 
model with a factor for treatment group and a covariate for the baseline score. 
5.4.2 Secondary efficacy endpoint display 
All secondary endpoints will be summarized by visit and treatment group using descriptive 
statistics (i.e., number of observations, mean, median, SD, minimum, and maximum for 
continuous endpoints; number and percentages for categorical endpoints).  
5.4.3 Other efficacy endpoint display 
The display of the other efficacy endpoints is similar to that of the secondary endpoints. 
Additionally, the correlation between the primary and secondary efficacy endpoints 
(restricted to Week 12) versus the change in disease severity from baseline to Week 12 as 
assessed by the physician 
 as well as by the patient 
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5.7 Safety and tolerability endpoints  
Safety analyses will be conducted on the ATS. The treatment-emergent period for the 
safety assessments is defined as the time from the first administration of study treatment to 
Visit 7 (EOS) except for ECG (up to Visit 6, EOT).  
All AEs and SAEs will be coded using MedDRA (Version 20.0 or a more recent version, 
if available). ECG abnormalities will be coded using CDISC SDTM terminology.  
All safety and tolerability data will be listed by treatment group and subject number. 
5.7.1 Adverse events 
Treatment-emergent AEs will be tabulated by primary system organ class (SOC), preferred 
term (PT), and treatment group. The number (%) of subjects who experienced AEs coded 
with the same PT will be displayed (in descending order according to the incidence). 
Treatment-emergent AEs will also be tabulated by severity and by relationship to study 
treatment by SOC and PT.  
AEs leading to premature discontinuation of study treatment will be summarized in a 
similar manner to that used for AEs. Reasons for premature discontinuation of study 
treatment will be listed, in particular to assess whether treatment discontinuation was 
caused by corticosteroid administration for NP and/or surgery for NP. 
Treatment-emergent SAEs and deaths will be summarized in a similar manner to that used 
for AEs. SAEs/deaths occurring before study treatment initiation or after EOS will be 
listed. 
5.7.2 Vital signs 
At each time point, absolute values and change from baseline of supine BP and pulse rate 
will be summarized with mean, median, SD, minimum, and maximum values. The number 
(%) of out-of-range values (based on available observations) will be presented. Values 
outside the reference range will be flagged in the listing. 
5.7.3 ECG recordings 
Treatment-emergent ECG abnormalities will be summarized and presented in a similar 
manner to that used for AEs.  
At each time point, absolute values and change from baseline of ECG numeric variables 
will be summarized using descriptive statistics. The number of available observations will 
be presented.  
5.7.4 Clinical laboratory tests 
At each time point, absolute values and change from baseline of clinical laboratory 
variables will be summarized with mean, median, SD, minimum, and maximum values. 


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The number (%) of out-of-range values (based on available observations) will be presented. 
Values outside the investigator’s normal range will be flagged in the listing. 
Treatment-emergent marked laboratory abnormalities will be summarized for each 
laboratory variable. The sponsor’s internal guidelines will be used for the standardization 
of numeric values obtained from different laboratories and/or using different normal 
ranges. Standard numeric laboratory variables will be transformed into standard units. 
Absolute values and changes in laboratory values converted to standardized units during 
the course of the study will be summarized by computing the usual location and scale 
statistics by period and treatment group.  
5.8 Exposure to study treatment 
Duration of randomized treatment (i.e., date of last intake minus date of first intake plus 
one day) will be summarized by treatment group in the ATS. 
5.9 Baseline variables and concomitant medications 
These analyses will be performed for the ATS. 
Continuous demographic variables (e.g., age, weight, BMI) will be summarized by 
descriptive statistics. Categorical demographic characteristics (e.g., sex, race) will be 
summarized by counts and percentages. Other baseline subject characteristics will only be 
listed. 
Previous and concomitant medications will be coded according to the WHO Drug code and 
the Anatomical Therapeutic Chemical class code (Version March 2018, or a more recent 
version, if available). Concomitant medications will be listed by treatment group and 
subject number. 
All reported medical history conditions will be coded using MedDRA (Version 20.0 or a 
more recent version, if available). Concomitant medications will be listed by treatment 
group and subject number. 
5.10 Exploratory analyses 
Exploratory, data-driven analyses may be performed, with the caveat that any statistical 
inference will not have confirmatory value. 
5.11 Interim analyses 
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6 
PROCEDURES AND GOOD CLINICAL PRACTICE 
6.1 Procedures 
6.1.1 Protocol amendments 
Any change to a protocol must be an amendment if the documents have already been 
submitted to IECs/IRBs or health authorities. An amendment could therefore occur before 
or after the approval of these documents by IECs/IRBs or health authorities. Each 
amendment must be documented in writing and approved by the sponsor, and must be 
reviewed by the investigator. 
Changes to the Core Subject Information and Informed Consent requested by IECs/IRBs 
are not considered to be formal amendments, as long as they do not significantly change 
the core document or affect the protocol. 
6.1.1.1 Non-substantial amendment 
Purely administrative or minor logistical changes require only a non-substantial 
amendment. Such changes include but are not limited to changes in study staff or contact 
details (e.g., the sponsor instead of CRO monitors), or minor changes in the packaging or 
labeling of study treatment.  
The implementation of a non-substantial amendment may be undertaken with or without 
notification to the appropriate IECs/IRBs and health authorities (subject to national 
regulations). It does not require their approval.  
6.1.1.2 Substantial amendment 
A substantial amendment is required for significant changes. These include, but are not 
limited to, new data affecting the safety of subjects, and changes to the objectives or 
endpoints of the study, eligibility criteria, dose regimen, study assessments/procedures, or 
treatment or study duration, with or without the need to modify the Core Subject 
Information and Informed Consent. 
Substantial amendments must be approved by the appropriate IECs/IRBs, and in some 
jurisdictions by the health authorities. The implementation of a substantial amendment may 
only occur after formal approval by the appropriate IECs/IRBs and/or health authorities, 
and must be signed by the investigators. 
6.1.1.3 Urgent amendment 
An urgent amendment might become necessary to preserve the safety of the subjects 
included in the study. The requirements for approval must not prevent any immediate 
action being taken by the investigator or the sponsor in the best interests of the subjects. If 
deemed necessary, an investigator may therefore implement an immediate change to the 
protocol for safety reasons, and in such exceptional cases the implementation of urgent 


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amendments will occur before submission to, and approval by, IECs/IRBs and health 
authorities.  
In such cases, the investigator must notify the sponsor within 24 hours. IECs/IRBs and 
health authorities must be notified immediately in writing. A related substantial 
amendment will be prepared and submitted by the sponsor to the appropriate IECs/IRBs 
and health authorities within 10 working days of receiving the notification.  
6.1.2 Monitoring 
Monitoring of this study is the responsibility of the sponsor. The sponsor’s monitor must 
contact and visit the investigator regularly, and must be allowed, on request, to have access 
to all study-related documents and facilities used in the study, as well as all source 
documents needed, to verify the entries on the eCRFs; provided that subject confidentiality 
is maintained in agreement with local regulations. It is the monitor’s responsibility to 
inspect the eCRFs at regular intervals throughout the study, to verify the adherence to the 
protocol and the completeness, consistency, and accuracy of the data being entered on 
them.  
The sponsor’s monitoring standards require full verification for the presence of informed 
consent, adherence to the inclusion/exclusion criteria, documentation of the study 
treatment dispensing, AEs, and SAEs. The amount of verification of other relevant safety, 
tolerability, PK, and PD endpoints will be defined based on the study objectives; the extent 
of additional checks for the consistency of the source data with the eCRFs will be discussed 
before the monitoring visit by the monitor and the clinical pharmacologist, and documented 
in the corresponding monitoring guideline. 
The investigator must ensure that subject anonymity will be maintained. On all documents 
submitted to the sponsor, subjects must not be identified by their names and date of birth, 
but by subject number only. The investigator must keep a subject identification log 
showing the subject number, the subject’s name, date of birth, and address or any other 
locally accepted identifiers. Documents identifying the subjects (e.g., subjects’ signed ICF 
must not be sent to the sponsor, and must be kept by the investigator in strict confidence. 
The investigator and sub-investigators agree to cooperate with the monitor(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 center, the investigator is responsible 
for contacting that hospital in order to document the SAE. 
The investigator must supply the sponsor on request with any required background data 
from the study documentation or clinic records. This is particularly important when errors 
in data transcription into eCRFs are suspected. In the event of special problems and/or 


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government/regulator queries, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
An initiation visit will be performed before the site before the first subject is screened. 
Following the initiation visit, a copy of the completed initiation visit report and follow-up 
letter will be provided to the investigator and filed in the ISF. 
The study treatment will be shipped to the site upon approval of the required essential 
documents.  
Monitoring visits and contacts will occur at regular intervals thereafter, and a close-out 
visit will be performed after study database closure. 
6.1.3 Data management 
6.1.3.1 Data collection 
A subject Screening and Enrollment Log must be completed for all subjects, both eligible 
and non-eligible, with the reasons for exclusion where applicable. 
Electronic Data Capture (EDC) via eCRFs (
 
 will be used for this study. eCRFs will be made 
available by Idorsia. For each subject who received at least one administration of study 
treatment, an eCRF must be completed and signed electronically by the investigator or sub-
investigator. This also applies to those subjects who fail to complete the study. If a subject 
withdraws from the study, the reason must be noted on the eCRF.  
Study data will be collected either by the investigator or by clinical research staff on paper 
source data documents and entered by the site staff into the eCRFs in a timely manner or 
transferred electronically and loaded into the eCRFs by Idorsia Data Management at 
specified time points. The eCRFs must be kept up-to-date so that they reflect the latest 
observations on the enrolled subjects. 
All source documents will be retained by the clinical site. Photocopies of completed source 
documents will be provided only if essential (i.e., for regulatory purposes) at the request of 
the sponsor. In accordance with ICH-GCP, the location of data identified as source data 
will be specified on the Source Document Identification List. The investigator/delegate 
must confirm by electronic signature that all data entries in the eCRFs are accurate and 
correct. All eCRF entries, corrections, and alterations must be made by the investigator or 
other, authorized, study site personnel and only by individuals who have received training 
on the EDC system. Site staff may be allowed access to the system only after training is 
completed. Training must be documented and a log of all EDC users and their rights within 
the system be maintained. 


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All source document forms must be completed using a black ballpoint pen, and must be 
legible. Errors must be crossed out but not obliterated, the correction inserted (if necessary 
the reason must be noted), and the change initialed and dated by the investigator, 
sub-investigator, or study nurse. 
After database lock, a CD including printouts of filled eCRFs for all subjects will be 
provided to the site (for contact details, pages 2 and 3). The investigator will have read-only 
access to the eCRF data until receipt of this CD. 
6.1.3.2 Data management and quality control 
Data management is the responsibility of Idorsia.  
The data entered into the EDC system will be systematically checked by Idorsia and site 
staff, using error messages from validation programs and database listings. All queries are 
raised and answered electronically within the EDC system. Once all queries are resolved, 
the authorized physician will review and electronically sign the eCRFs. 
With the eCRF, the data checks made for consistency and plausibility will be done via the 
EDC system or performed manually by Data Management as defined in the Data Validation 
Specifications. 
Sponsor monitoring is performed on-site, reviewing the data for correctness, plausibility, 
and completeness. 
Safety laboratory samples will be processed by the local laboratory and the results will be 
sent by the sites to the external service provider, 
 who will electronically send the 
data to Idorsia to load into the clinical database. 
A data review will be performed by trained staff of Idorsia before database closure. 
SAEs occurring after ICF signature and up to EOS will be reconciled between the clinical 
database at Idorsia and the Idorsia Drug Safety database before database closure. 
The PD data will be stored separately and will be merged with the clinical database. 
Therefore, the availability of these results will not affect study closure.  
The PK samples will be processed by the bioanalytical laboratory at Idorsia (Preclinical 
Pharmacokinetics and Metabolism) and the results will be sent electronically to Idorsia. 
The PK data will be stored separately and will be merged with the clinical database. 
Therefore, the availability of these results will not affect study closure. 
After the clinical database has been declared complete and accurate, the clinical database 
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by the Idorsia clinical pharmacologist and approved by the Idorsia Head of Clinical 
Pharmacology. 
6.1.4 Recording of data and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: investigator’s 
file, and subject clinical source documents.  
These records must be kept by the investigator for as long as is necessary to comply with 
Idorsia’s requirements (e.g., 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 investigational site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and Idorsia to store these documents outside the site, so that they 
can be retrieved in the event of a regulatory inspection. No study document should be 
destroyed without prior written approval from Idorsia. Should the investigator wish to 
assign the study records to another party, or move them to another location, Idorsia must 
be notified in advance.  
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the monitor has been provided with personal and restricted 
access to study subjects only, to verify consistency between electronic source data and the 
eCRF during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the monitor 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 monitor. 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 subject’s data. The 
printouts will be considered as the official clinical study records.  
In order to verify that the process the site uses to prepare certified copies is reliable, the 
monitor 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 monitor does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 


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subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Idorsia’s instructions. If it were not possible for the 
monitor 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. The printouts should be filed 
with the subject medical records. 
The site master file will contain all the essential documents that are required to always be 
up-to-date and filed at site as per ICH-GCP section 8. 
The site master file will include a table of contents listing the essential documents. All 
study related documentation must be maintained in the site master file. 
In some cases, exceptions can be discussed with the monitor regarding the filing of the 
study documents outside the site master file. 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 site master file. 
The site master file must be stored in a secure and restricted-access area during and after 
the study. It must be kept by the site for as long as needed to comply with any applicable 
rules and regulations, ICH-GCP as well as instructions from Idorsia. If the site needs to 
transfer the site master file to another location and/or if site facility can no longer store the 
site master file the investigator must inform Idorsia immediately.  
If the investigator will change, or if the site will relocate, the monitor must be notified as 
soon as possible.  
6.1.5 Audit 
Idorsia’s Quality Assurance, Systems & Compliance 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 Idorsia’s requirements (e.g., standard operating procedures) will 
also be verified. Prior to initiating this audit, the investigator will be contacted by Idorsia 
to arrange a time for the audit.  
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
6.1.6 Inspections 
Health authorities and/or IEC/IRB may also wish to conduct an inspection of Idorsia’s 
clinical study (during the study or after its completion).  


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Should an inspection be requested by a health authority and/or IEC/IRB, the investigator 
must inform Idorsia immediately, (usually via the monitor), that such a request has been 
made.  
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g., subject records) and study facilities. 
6.1.7 Handling of study treatment(s) 
The sponsor will supply all study treatment(s) to the site according to local regulations. 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the study treatment labels. The site must maintain an accurate 
record of the shipment and dispensing of study treatment(s) on an accountability form, 
which must be given to the monitor at the end of the study. An accurate record of the date 
and amount of study treatment(s) dispensed to each subject must be available for inspection 
at any time. 
All study treatment supplies are to be used only in accordance with this protocol and not 
for any other purpose. The responsible person must not destroy any study treatment labels 
or unused study treatment supply. On termination of the study, the monitor will check 
accountability of all used and unused study treatment. 
Used and unused study treatment containers must be returned to the sponsor depot once 
study treatment accountability is final and has been checked by the sponsor or its deputy, 
and written permission for destruction has been obtained from the sponsor. 
6.1.8 Publication and reporting of study results 
Study results will be documented in a clinical study report that will be signed by Idorsia 
representatives and the investigator. 
The investigator will have the opportunity to review the analysis of the data and to discuss 
the interpretation of the study results with Idorsia prior to publication. 
The sponsor 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. 
In accordance with 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 publication in a peer-reviewed journal. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 


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 Substantial contributions to: the conception or design of the study, or the acquisition, 
analysis or interpretation of data; and 
 Drafting of the publication or critical review for important intellectual content; and  
 Providing final approval of the version to be published; and 
 Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.  
The list of authors of any publication of study results may include representatives of 
Idorsia, and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
Idorsia for review at least 30 days prior to submission for publication or presentation. Upon 
review, Idorsia may provide comments, and may also request alterations and/or deletions 
for the sole purpose of protecting its confidential information and/or patent rights. Neither 
the institution nor the investigator should permit publication during such a review period. 
6.1.9 Disclosure and confidentiality 
By signing this protocol, the investigator agrees to keep all information provided by the 
sponsor in strict confidence, and to request similar confidentiality from his or her staff and 
the IEC/IRB. Study documents provided by the sponsor (including IBs, protocols, eCRFs, 
and other protocol-related documents) will be stored appropriately to ensure their 
confidentiality. The information provided by the sponsor to the investigator may not be 
disclosed to others without direct written authorization from the sponsor, except to the 
extent necessary to obtain informed consent from subjects who wish to participate in the 
trial.  
6.1.10 Premature termination or suspension of the study 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
The study may be prematurely terminated if the sponsor decides to discontinue the 
development of ACT-774312 (continuation has become scientifically meaningless) or due 
to significant safety findings occurring in this study. 
If a study is prematurely terminated or suspended, the sponsor must promptly inform the 
investigator, the IECs/IRBs and health authorities, as appropriate, and provide the reasons 
for the termination or suspension.  
If the study is prematurely terminated or suspended for any reason, the investigator, in 
agreement with the sponsor, must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up. 


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In addition, if the investigator terminates or suspends a study without prior agreement from 
the sponsor, the investigator must promptly inform the sponsor and the IEC/IRB, and must 
provide the sponsor and the IEC/IRB with a detailed written explanation of the termination 
or suspension. 
If the IEC/IRB terminates or suspends its approval / favorable opinion of a study, the 
investigator must promptly notify the sponsor and provide the sponsor with a detailed 
written explanation of the termination or suspension. 
6.2 Good Clinical Practice 
6.2.1 Ethics and Good Clinical Practice 
Idorsia and the investigators will ensure that the study is conducted in full compliance with 
ICH-GCP guidelines, the principles of the “Declaration of Helsinki” and with the laws and 
regulations of the country in which the research is conducted.  
6.2.2 Ethics Committee / Institutional Review Board 
The investigator must submit this protocol and any related document provided to the 
subject (such as subject information used to obtain informed consent) to an IEC or IRB. 
Approval from the committee 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. A list of members participating in the 
meeting must be provided, including the functions of these members. If study staff were 
present, it must be clear that none of these persons voted. 
Modifications made to the protocol after receipt of the IEC/IRB approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 6.1.1]. 
6.2.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH-GCP guidelines and local regulations from each individual participating in this study 
and/or legal representative. The investigator/delegate must explain to subjects that they are 
completely free to refuse to enter the study, or to withdraw from it at any time for any 
reason. 
The ICF will be provided in the country local language(s). 
Site staff authorized to participate to the consent process and/or to obtain consent from the 
subject and/or legal representative will be listed on Idorsia Delegation of Authority (DoA) 
form. A study physician must always be involved in the consent process.  




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APPENDICES