Clinical trial NCT03541174
Conditions: Resistant Hypertension
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2018-06-18; Completion date: 2022-04-25
Enrollment: 730 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to show the blood pressure lowering effect of aprocitentan, a new drug, when added to other anti-hypertensive drugs of patients with difficult to control (resistant) high blood pressure (hypertension), and to show that blood pressure reduction is kept for long period of time.

Detailed description:
Participation in the study will be up to 68 weeks.

The study has 4 periods:

1. Screening period
2. Placebo run-in period
3. Randomized treatment period
4. Safety follow-up period

The screening period lasts between 4 and 12 weeks. It starts at the screening visit with the signing of the informed consent form (ICF) and ends the day before the participant enters the run-in period.

At least 4 weeks before the start of the run-in period, the background antihypertensive medication (except beta-blockers) of participants with a diagnosis of true resistant hypertension and having a mean trough sitting systolic blood pressure of equal to or greater than 140 mmHg measured by automated AOBPM will be standardized by switching to a fixed combination of a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan) and a diuretic (hydrochlorothiazide).

In case a beta-blocker is used as one of the background antihypertensive medications or for any other indication, this can be kept, with the provision that it has been initiated and the dose kept stable for at least 4 weeks prior to the screening visit and the dose kept stable until the end-of-treatment.

Following the screening period this study has a run-in period of 4 weeks. During this period, placebo will be administered in order to exclude potential placebo responders.

Following the run-in period eligible participants will enter the randomized treatment period. This period lasts for 48 weeks. It starts at randomization (i.e., Day 1 of the double-blind part) and ends at the end-of-treatment visit (i.e., at the end of the double-blind withdrawal part).

The randomized treatment period consists of 3 parts: Part 1 is double-blind, randomized, parallel-group and placebo-controlled and lasts 4 weeks. Part 2 is single-blind and single-arm and lasts for 32 weeks. Part 3 is a double-blind withdrawal, randomized, parallel-group and placebo-controlled and lasts for 12 weeks.

End-of treatment is at Week 48 (i.e., end of the double-blind withdrawal part). The safety follow-up starts on the day after the last dose of study treatment and ends 30 to 33 days after the last dose of study treatment.

Arms: arm 1: Participants will receive aprocitentan 25 mg, orally, once daily in the morning for 4 weeks. arm 2: Participants will receive aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks. arm 3: Participants will receive placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks. arm 4: After 4-weeks in the double-blind randomized part (Part 1), participants will received 25 mg aprocitentan, orally, once daily in the morning for 32 weeks. arm 5: After 32-weeks in the single-blind, single-arm part (Part 2), participants will be re-randomized and receive aprocitentan 25 mg, orally, once daily in the morning for 12 weeks. arm 6: After 32-weeks in the single-blind, single-arm part (Part 2), participants will be re-randomized and receive placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks.
Interventions: intervention 1: Aprocitentan 12.5 mg intervention 2: Aprocitentan 25 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Tablet, oral use intervention 2: Tablet, oral use intervention 3: Matching placebo tablet

Protocol documents:
SAP_002.pdf: 
Cover page 
Official Title: 
Multi-center, blinded, randomized, parallel-group, Phase 3 study with aprocitentan in 
subjects with resistant hypertension (RHT). 
ClinicalTrials.gov Identifier: 
NCT03541174 
Brief Title: 
A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to 
Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its 
Safety 
(PRECISION) 
Date of SAP document: 
6 April 2022 


TPL-100721_v02 
APROCITENTAN (ACT-132577) 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT 
ID-080A301 
PRECISION 
Multi-center, blinded, randomized, PaRallEl-group, Phase 3 study with aproCItentan in 
Subjects with ResIstant HypertensiON (RHT). 
Document Number: D-22.107 
6 April 2022 
Property of Idorsia Pharmaceuticals Ltd 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Idorsia Pharmaceuticals Ltd 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ........................................................... 6 
1 
INTRODUCTION ...................................................................................................... 10 
2 
STUDY DESIGN AND FLOW ................................................................................. 10 
2.1 
Study design ................................................................................................ 10 
2.2 
Study visit and assessment schedule ........................................................... 12 
2.3 
Overview of analysis periods ...................................................................... 17 
2.4 
Impact of the COVID-19 pandemic ............................................................ 17 
3 
OBJECTIVES ............................................................................................................ 17 
3.1 
Primary objective ......................................................................................... 17 
3.2 
Secondary objectives ................................................................................... 17 
3.3 
Other objectives ........................................................................................... 17 
4 
ANALYSIS SETS ...................................................................................................... 18 
4.1 
Definitions of analysis sets .......................................................................... 18 
4.1.1 
Screened set ..................................................................................... 18 
4.1.2 
Run-in set ......................................................................................... 18 
4.1.3 
All-randomized set ........................................................................... 18 
4.1.4 
Full analysis set ................................................................................ 18 
4.1.5 
Modified Full analysis set ................................................................ 18 
4.1.6 
Per-protocol analysis set .................................................................. 18 
4.1.7 
Modified Per-protocol analysis set .................................................. 19 
4.1.8 
Ambulatory blood pressure monitoring Full analysis set ................ 19 
4.1.9 
Modified ambulatory blood pressure monitoring Full analysis 
set ..................................................................................................... 19 
4.1.10 
Safety analysis set ............................................................................ 19 
4.1.11 
Restricted Safety analysis set ........................................................... 19 
4.1.12 
Modified Safety analysis set ............................................................ 19 
4.1.13 
Pharmacokinetic set ......................................................................... 20 
4.2 
Usage of the analysis sets ............................................................................ 20 
5 
STUDY SUBJECT VARIABLES AND ANALYSES .............................................. 21 
5.1 
Subject disposition ....................................................................................... 21 
5.1.1 
Study disposition .............................................................................. 21 
5.1.2 
Study completion/discontinuation ................................................... 22 


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5.1.3 
Study treatment completion/discontinuation ................................... 22 
5.2 
Protocol deviations ...................................................................................... 23 
5.3 
Exclusion from analysis data sets ................................................................ 23 
5.4 
Subject characteristics ................................................................................. 23 
5.4.1 
Demographics .................................................................................. 23 
5.4.2 
Disease characteristics ..................................................................... 24 
5.4.3 
Medical history ................................................................................ 24 
5.4.4 
Previous and concomitant therapies ................................................ 25 
5.5 
Study treatment duration and compliance ................................................... 26 
5.5.1 
Treatment duration ........................................................................... 26 
5.5.2 
Compliance with study treatment .................................................... 27 
6 
EFFICACY VARIABLES AND ANALYSES .......................................................... 28 
6.1 
Overall testing strategy ................................................................................ 28 
6.2 
Primary endpoint analysis ........................................................................... 29 
6.2.1 
Variable ............................................................................................ 29 
6.2.2 
Intercurrent events and choice of estimand ..................................... 29 
6.2.3 
Main analysis for the primary endpoint ........................................... 30 
6.2.4 
Sensitivity analyses for the primary endpoint .................................. 30 
6.2.5 
Supportive analyses for the primary endpoint ................................. 31 
6.2.6 
Subgroup analyses for the primary endpoint ................................... 31 
6.2.7 
Impact of the COVID-19 pandemic on the analysis of primary 
endpoint ........................................................................................... 32 
6.3 
Key secondary endpoint analysis ................................................................ 32 
6.3.1 
Variable ............................................................................................ 32 
6.3.2 
Intercurrent events and choice of estimand ..................................... 32 
6.3.3 
Main analysis for the key secondary endpoint ................................. 33 
6.3.4 
Sensitivity analyses for the key secondary endpoint ....................... 33 
6.3.5 
Supportive analyses for the key secondary endpoint ....................... 34 
6.3.6 
Subgroup analyses for the key secondary endpoint ......................... 34 
6.3.7 
Impact of the COVID-19 pandemic on the analysis of key 
secondary endpoint .......................................................................... 34 
6.4 
Other secondary efficacy endpoints analyses .............................................. 34 
6.4.1 
Variables .......................................................................................... 34 
6.4.2 
Analyses ........................................................................................... 35 
6.5 
Other efficacy endpoints .............................................................................. 36 
6.5.1 
Variables .......................................................................................... 36 
6.5.2 
Analyses ........................................................................................... 37 
6.6 
Overview of efficacy analyses ..................................................................... 39 
6.7 
Analysis of pharmacokinetic variables ........................................................ 43 


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7 
SAFETY VARIABLES AND ANALYSES .............................................................. 43 
7.1 
Adverse events ............................................................................................. 43 
7.1.1 
Variables .......................................................................................... 43 
7.1.1.1 
Treatment-emergent adverse events ....................................... 43 
7.1.1.2 
Relationship of treatment-emergent adverse events ............... 44 
7.1.1.3 
Intensity of treatment-emergent adverse events ..................... 44 
7.1.1.4 
Serious adverse events ............................................................ 44 
7.1.1.5 
Adverse events leading to discontinuation of study 
treatment ................................................................................. 44 
7.1.1.6 
Adverse events of special interest (AESIs) ............................ 44 
7.1.2 
Analysis ........................................................................................... 45 
7.2 
Death ............................................................................................................ 46 
7.3 
Laboratory tests ........................................................................................... 46 
7.3.1 
Variables .......................................................................................... 46 
7.3.2 
Analysis ........................................................................................... 47 
7.4 
Electrocardiography ..................................................................................... 47 
7.4.1 
Variables .......................................................................................... 47 
7.4.2 
Analysis ........................................................................................... 48 
7.5 
Vital signs and body weight ........................................................................ 48 
7.5.1 
Variables .......................................................................................... 48 
7.5.2 
Analysis ........................................................................................... 48 
7.6 
Other safety variables and analyses ............................................................. 48 
7.6.1 
Treatment-emergent MACE and MACE-plus ................................. 48 
7.6.2 
Increase in dose of existing diuretic or addition of new diuretic 
due to fluid retention ........................................................................ 49 
7.6.3 
Analysis of biomarker variables ...................................................... 49 
7.7 
Overview of safety analyses ........................................................................ 50 
8 
GENERAL STATISTICAL METHODOLOGY ....................................................... 51 
8.1 
General rules for data presentations ............................................................ 51 
8.2 
Analysis details ............................................................................................ 53 
8.2.1 
Mixed model for repeated measurements ........................................ 53 
8.2.2 
Controlled imputation assuming missing not at random ................. 54 
8.2.3 
Tipping point analysis assuming missing not at random ................. 56 
8.2.4 
Two-step Cox model ........................................................................ 58 
8.2.5 
Control/response analysis ................................................................ 59 
9 
INTERIM ANALYSES ............................................................................................. 59 
10 GENERAL DEFINITIONS AND DERIVATIONS .................................................. 59 
10.1 
Analysis periods and visit windows ............................................................ 59 


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10.1.1 
Analysis periods ............................................................................... 59 
10.1.2 
Visit windows .................................................................................. 60 
10.2 
Handling of incomplete dates ...................................................................... 62 
10.2.1 
Adverse events ................................................................................. 62 
10.2.2 
Concomitant therapies ..................................................................... 63 
11 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL ................................................................................................ 64 
12 LIST OF TABLES, LISTINGS AND FIGURES ...................................................... 65 
13 REFERENCES ........................................................................................................... 65 
14 APPENDICES ............................................................................................................ 67 
14.1 
Revision history ........................................................................................... 67 
14.2 
Thresholds for marked abnormalities .......................................................... 70 
14.3 
Definition of adverse events of specific interest ......................................... 72 
14.4 
Definition of diuretic and antihypertensives medications ........................... 73 
 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule up to Randomization ................................ 13 
Table 2 
Visit and assessment schedule from start of DB treatment period up to 
EOS ........................................................................................................... 15 
Table 3 
Role of the analysis sets ............................................................................ 20 
Table 4 
Summary of efficacy analyses ................................................................... 40 
Table 5 
Summary of safety analyses ...................................................................... 50 
Table 6 
Visit windows ............................................................................................ 61 
Table 7 
Imputation rules for an incomplete or missing AE date ............................ 62 
Table 8 
Imputation rules for an incomplete or missing concomitant therapy or 
antihypertensive therapy date .................................................................... 63 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design .............................................................................................. 11 
Figure 2 
Testing strategy ......................................................................................... 29 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
ABPM 
 
Ambulatory blood pressure monitoring 
ACEi 
 
Angiotensin-converting enzyme inhibitor 
AE 
 
Adverse event 
AESI 
 
Adverse event of special interest 
aFAS  
Ambulatory blood pressure monitoring Full analysis set 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
AOBPM  
Automated office blood pressure measurement 
ARB  
Angiotensin receptor blockers 
AST  
Aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
BMI  
Body mass index 
BOCF  
Baseline observation carried forward 
BP  
Blood pressure 
CAC  
Central Adjudication Committee 
CCB  
Calcium channel blockers 
CDISC  
Clinical Data Interchange Standards Consortium 
CI  
Confidence interval 
CKD  
Chronic Kidney Disease 
CKD-EPI  
Chronic Kidney Disease Epidemiology Collaboration 
CMH  
Cochran-Mantel-Haenszel 
COVID-19  
Coronavirus disease 2019 
CR  
Copy Reference 
DB   
Double‑blind 
DBP  
Diastolic blood pressure 
DB-WD  
Double‑blind Withdrawal 
ECG  
Electrocardiogram 
eCRF  
Electronic Case Report Form 


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eGFR  
Estimated glomerular filtration rate 
EMA  
European Medicines Agency 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
EudraCT  
European Clinical Trials Database 
eTMF  
Electronic trial master file 
FAS  
Full analysis set 
FDA  
Food and Drug Administration (US) 
FU  
Follow-up 
HBP  
Home Blood Pressure 
HR  
Heart rate 
ICH  
International Council for Harmonisation 
IRT  
Interactive Response Technology 
IXRS  
Interactive Voice/Web Response System 
J2R  
Jump to Reference 
LOCF  
Last observation carried forward 
LSM  
Least Squares Mean 
MACE  
Major adverse cardiac event(s) 
maFAS  
Modified ambulatory blood pressure monitoring Full analysis set 
MAR  
Missing at random 
MedDRA  
Medical Dictionary for Drug Regulatory Activities 
mFAS  
Modified Full analysis set 
MI  
Multiple imputation 
MNAR  
Missing not at random 
mPPS  
Modified Per-protocol analysis set 
MRA  
Mineralocorticoid receptor antagonist 
mSAF  
Modified Safety analysis set 
NT-proBNP  
N-terminal pro-brain natriuretic peptide 
OR  
Odds ratio 


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PD  
Protocol deviation 
PK  
Pharmacokinetic(s) 
PPS  
Per-protocol analysis set 
PRECISION  
PaRallEl-group, Phase 3 study with aproCItentan in Subjects with 
ResIstant HypertensiON (RHT) 
PT  
Preferred term 
QTcB  
QT interval corrected according to Bazett’s formula 
QTcF  
QT interval corrected according to Fridericia’s formula 
RHT  
Resistant hypertension 
RI  
Run-in 
RIS  
Run-in set 
RND  
All-randomized set 
rSAF  
Restricted Safety analysis set 
SAE  
Serious adverse event 
SAF  
Safety analysis set 
SAP  
Statistical analysis plan 
SB  
Single-blind 
SBP  
Systolic blood pressure 
SCR  
Screened set 
SD  
Standard deviation 
SDTM  
Study Data Tabulation Model 
SI  
Standard International 
SiDBP  
Sitting diastolic blood pressure 
SiSBP  
Sitting systolic blood pressure 
SMQ  
Standardised MedDRA Query 
SOC  
System organ class 
UACR  
Urine albumin-to-creatinine ratio 
ULN  
Upper limit of normal 
WD  
Withdrawal 


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WHO  
World Health Organization 
 
 


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1 
INTRODUCTION 
This SAP is to describe the planned statistical analyses for study ID-080A301 
(PRECISION) in detail. 
This SAP (Version 3) is based on Version 3 of the ID-080A301 protocol, dated 
27 February 2020 [D-20.008], and its addendum, dated 8 April 2020 [D‑20.063]. At the 
time of writing of this SAP Version 3, all subjects had been randomized. This SAP does 
not address the analysis of biomarkers characterizing the endothelin system activity, which 
will be addressed in a separate SAP. 
Following comments received from regulatory agencies on SAP Version 2, the primary 
estimand was changed: a treatment policy strategy is now used in the main analysis instead 
of a hypothetical strategy estimand. The protocol, however, was not amended as the 
comments were received at a late stage and the change in estimand did not impact the 
clinical conduct of the study. 
Source data for the analyses will be provided as SAS® data sets according to the CDISC 
SDTM. Analysis data sets will be derived as SAS® data sets according to the CDISC 
Analysis Data Model, IG version 1.1 or higher. Analyses will be illustrated using code 
based on SAS® Version 9.4. 
2 
STUDY DESIGN AND FLOW 
2.1 Study design 
ID-080A301 is a study in subjects with RHT who are on a standardized background 
antihypertensive therapy of a fixed combination of a calcium channel blocker, an 
angiotensin 
receptor 
blocker, 
and 
a 
diuretic 
(amlodipine, 
valsartan, 
and 
hydrochlorothiazide). The main inclusion criterion at Randomization is a mean SiSBP 
≥ 140 mmHg, as measured by AOBPM. 
The study consists of four periods: a screening period, a placebo RI period, a randomized 
treatment period and a safety FU period. The study design is displayed in Figure 1. 


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Figure 1 
Study design 
 
EOT = End-of-Treatment; FU = follow-up; V = visit. 
The randomized treatment period lasts for 48 weeks [until EOT, as displayed in Figure 1]. 
The purpose of this period is to evaluate the primary and secondary objectives of the study. 
This period consists of three sequential parts:  
• In the first DB part of 4 weeks, subjects will be randomized to aprocitentan 25 mg, 
aprocitentan 12.5 mg or placebo in a 1:1:1 ratio. 
• In the second SB part of 32 weeks, all subjects will receive aprocitentan 25 mg. 
• In the third DB-WD part of 12 weeks, subjects will be re-randomized at Week 36 to 
aprocitentan 25 mg or placebo in a 1:1 ratio. 
The EOT visit will take place at Week 48 (i.e., end of DB-WD part) or earlier in the event 
of premature discontinuation of study treatment.  
Approximately 4000 subjects were expected to be screened in order to enroll 
approximately 1500 subjects with a diagnosis of RHT into the SB placebo RI period. At 
least 600 subjects were to be randomized and at least 380 subjects were expected to be 
re‑randomized in the DB‑WD part. At least 300 subjects were expected to complete the 
study (including the 30-day safety FU period). The study was to be conducted at 
approximately 100 sites in approximately 20 countries. 
The sponsor planned to look at the drop-out rate (between Randomization and 
Re-randomization) nine months after the randomization of the 200th subject.  
If the observed drop-out rate was such that the expected number of subjects to be 
re-randomized in the DB-WD part was less than 380, the number of subjects randomized 
could have been increased to maintain at least 85% power for the DB-WD part (which is 


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achieved when 324 subjects are re-randomized). It appeared that the drop-out rate was 
lower than expected, so no sample size increase was needed to compensate for drop-out. 
Ultimately, 730 subjects were randomized. The overrunning was caused by the addition of 
sites and countries in 2020 meant to compensate for the lower recruitment due to the 
Covid‑19 pandemic. In order to give these new sites a reasonable chance to contribute to 
the study, the timelines were prolonged, which, combined with a surge in screening when 
the EOS was announced, lead to an over-recruitment. The study was finally conducted at 
193 sites in 22 countries.  
2.2 Study visit and assessment schedule 
The visit and assessment schedules up to Randomization and from start of DB treatment 
period up to EOS are given in Table 1 and Table 2, respectively. 


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Table 1 
Visit and assessment schedule up to Randomization 
PERIODS 
Name / Duration 
Screening 
4-12 weeks 
Run-in  
4 weeks 
 
VISITS1 
Number 
1 
1.112 
2 
3 
4 
Time 
Week –16 to Week –8 
Week –8 
at the latest 
Week –4 
Week –2 
End of Run-in 
Randomization 
Additional visits as needed 
Day –28 
(4 d) 
Day −14 
(2 d) 
Day –1 
Day 1 
Informed consent 
X 
 
 
 
 
 
Eligibility including confirmation of diagnosis of true RHT 
X 
X 
X13 
X13 
X15 
 
Demographics / Medical history 
X 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Body weight, height2 
X 
X 
X 
X 
X16 
 
12-lead ECG3 
X 
 
 
 
X16 
 
Laboratory tests4  
X 
 
 
 
X16,17 
 
Serum pregnancy test 
X 
X 
X 
 
X16,17 
 
Urinalysis5 
 
 
  
  
X16 
 
Urine sampling to monitor treatment adherence6 
 
 
X6 
X  
X16 
 
AOBPM (incl. HR) 
X 
X 
X 
X 
X 
 
Home BP monitoring7 
 
 
ABPM 
 
 
 
 
X16 
X 
Blood sampling for biomarkers8 
X 
 
 
 
X 
 
Accountability of study treatment and standardized background 
antihypertensive therapy9 
 
 
X 
X 
X16 
 
Dispensing/return of study treatment and standardized background 
antihypertensive therapy10 
 
X 
X14 
 
X 
X 
SAE11 and AE11 
X 
X 
X 
X 
X 
X 
1 Unscheduled visits may be performed at any time during the study. 
2 Body weight is measured at each visit with the same weight scale. Height is only measured at Screening. 
3 ECGs are read centrally. 
4 Hematology and clinical chemistry. 
5 For UACR determination. 


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6 Urine sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy). No urine sample to be collected for subjects who do not 
fulfill Run-in eligibility criteria. 
7 Upon investigator’s judgment, a home BP monitoring device will be dispensed, if necessary.  
8 Blood sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy).  
9 Drug accountability (pill counts of study treatment and standardized background antihypertensive therapy). 
10 Study treatment including standardized background antihypertensive therapy should be brought back to each visit. 
11 All AEs and SAEs that occur after signing the informed consent form and up to 30 days after study treatment discontinuation must be reported. 
12 Switch to the standardized background antihypertensive therapy. Visit 1.1 may be at the same day as Visit 1. Additional visits may be performed for further assessments (e.g., to 
adjust the dose of the standardized background antihypertensive therapy, taking urine samples to monitor adherence).  
13 Run-in eligibility criteria. 
14 From this time point onwards the dose of the standardized background antihypertensive therapy must be kept stable. 
15 Randomization eligibility criteria. 
16 For subjects who permanently discontinue prior to Randomization due to any reason or do not fulfill the randomization eligibility criteria, these tests are not mandatory.  
17 Two samples will be drawn: one sample for the central laboratory and one sample for the local laboratory to measure hemoglobin, creatinine (to determine eGFR), AST/ALT, and 
a pregnancy test to confirm eligibility of subjects for randomization.  
 
ABPM = ambulatory blood pressure monitoring; AE = adverse event; ALT = alanine aminotransferase; AOBPM = automated office blood pressure measurement; AST = aspartate 
aminotransferase; BP = blood pressure; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HR = heart rate;; RHT = resistant hypertension; SAE = serious 
adverse event; UACR = urine albumin-to-creatinine ratio. 
 
 


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Table 2 
Visit and assessment schedule from start of DB treatment period up to EOS 
PERIODS 
Name / 
Duration 
DB Treatment 
4 weeks 
SB Treatment 
32 weeks 
DB-WD Treatment 
12 weeks 
FU12 
30 days 
VISITS1 
Number 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Time 
Week 2 
Week 4 
Week 6 
Week 12 Week 20 Week 28 
Week 36 
Week 38 
Week 40 
Week 44 
EOT11 
Week 48 
EOS 
(EOT+30 d) 
Day 14 
(2 d) 
Day 28 
(2 d) 
Day 
29 
Day 42 
(2 d) 
Day 84  
(10 d) 
Day 140  
(10 d) 
Day 196  
(10 d) 
Day 252 
(12 d) 
Day 
253 
Day 266 
(4 d) 
Day 280  
(4 d) 
Day 
281 
Day 308 
(4 d) 
Day 336 
(4 d) 
Day 366 
(+3 d) 
Physical examination 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
Body weight2 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
12-lead ECG3 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
X 
Laboratory tests4 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
Urinalysis5 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
Urine sampling to monitor treatment adherence6 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
AOBPM (incl. HR) 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Home BP monitoring7 
 
ABPM 
 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
 
 
 
Blood sampling for PK8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for biomarkers8 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
Accountability of study treatment and 
standardized background antihypertensive 
therapy9 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Dispensing/return of study treatment and 
standardized background antihypertensive 
therapy  
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
SAE10 and AE10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
1 Unscheduled visits may be performed at any time during the study.  
2 Body weight is measured at each visit with the same weight scale.  


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3 ECGs are read centrally. 
4 Hematology and clinical chemistry including NT-proBNP and serum pregnancy test. During SB aprocitentan part, urine pregnancy tests will be performed monthly (i.e., between 
scheduled visits) at home with kits that are provided to the subject. 
5 For UACR determination. 
6 Urine sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy).  
7 Upon investigator’s judgment, a home BP monitoring device will be dispensed, if necessary.  
8 Blood sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy). 
9 Study treatment including standardized background antihypertensive therapy should be brought back at each visit for drug accountability (pill counts). 
10 All AEs and SAEs that occur after signing the informed consent form and up to 30 days after study treatment discontinuation must be reported. 
11 Randomized subjects who prematurely discontinue prior to Week 48/Visit 15 should have an EOT visit scheduled no later than 7 days after the last dose of randomized study 
treatment.  
12 For subjects who discontinued during the RI period, this will be a phone call to collect adverse events and concomitant medications only. 
 
ABPM = ambulatory blood pressure monitoring; AE = adverse event; AOBPM = automated office blood pressure measurement; BP = blood pressure; DB = double-blind; 
ECG = electrocardiogram; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; HR = heart rate; NT-proBNP = N-terminal pro-brain natriuretic peptide; 
PK = pharmacokinetic(s); RI = run-in; SAE = serious adverse event; SB = single-blind; UACR = urine albumin-to-creatinine ratio; WD = withdrawal. 
 


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2.3 Overview of analysis periods 
The RI period starts at the date of the first dose of RI treatment and ends at the date of the 
last dose of RI treatment. 
The randomized treatment period is divided into three parts: DB, SB aprocitentan and 
DB-WD. The DB (SB, DB-WD, respectively) part starts at the DB (SB, DB-WD, 
respectively) treatment start date and ends at the DB (SB, DB-WD, respectively) treatment 
end date (collected on the Study Treatment Log). 
In some analyses the DB and SB aprocitentan parts are combined, indicated as ‘DB+SB 
part’. For details see Section 10.1.1. 
2.4  Impact of the COVID-19 pandemic  
Idorsia provided instructions and guidance in line with Health Authority guidelines (FDA, 
EMA and individual national health authorities) released in March 2020. These 
recommendations and instructions are summarized in an addendum of the protocol 
[D‑20.063]. The impact on the statistical analysis is addressed in Sections 2.4, 5.1.2, 5.1.3, 
5.2, 6.2.7, 6.3.7, 6.5.1 and 6.5.2 of this SAP.  
3 
OBJECTIVES 
3.1 Primary objective 
The primary objective of the study is to demonstrate the BP lowering effect of aprocitentan 
when added to standard‑of‑care in subjects with true RHT. 
3.2 Secondary objectives 
The secondary objectives of the study are: 
• To demonstrate that the effect of aprocitentan on BP is durable when added to 
standard‑of‑care in subjects with true RHT. 
• To evaluate the long-term safety and tolerability of aprocitentan in subjects with true 
RHT during 48 weeks of treatment. 
3.3 Other objectives 
• Evaluate steady-state trough plasma concentrations of aprocitentan after 4 weeks of 
treatment. 
• Evaluate the endothelin system activity and the effect of aprocitentan on micro- and 
macro‑vascular complications based on specific biomarkers.  


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4 
ANALYSIS SETS 
4.1 Definitions of analysis sets 
4.1.1 Screened set 
The SCR includes all subjects who have given informed consent to participate in the study 
and have a subject number. 
4.1.2 Run-in set 
The RIS includes all subjects from the SCR who received at least one dose of placebo in 
the RI period.  
4.1.3 All-randomized set 
The RND includes all subjects who were randomized. 
4.1.4 Full analysis set 
The FAS includes all subjects who were randomized and have a baseline SiSBP, measured 
by AOBPM at trough. Subjects will be evaluated according to their assigned study 
treatment in the DB part: aprocitentan 25 mg, aprocitentan 12.5 mg or placebo. 
4.1.5 Modified Full analysis set 
The mFAS includes all subjects from the FAS who were re-randomized in the DB-WD 
part of the study and who have a DB-WD baseline SiSBP, measured by AOBPM at trough. 
Subjects will be evaluated according to their assigned study treatment in the DB‑WD part: 
aprocitentan 25 mg or placebo. 
4.1.6 Per-protocol analysis set 
The PPS includes all subjects from the FAS without protocol deviations that potentially 
affect the primary endpoint. Reasons for exclusion from the PPS are: 
• DB treatment duration less than 21 days. 
• Use of at least one medication as per protocol deviation list code 04A04 and 04A07 or 
use of additional diuretic or rescue medication in DB part. 
• Compliance with DB treatment < 80% or > 120% [as calculated in Section 5.5.2]. 
• Compliance with standardized background antihypertensive therapy in DB part < 80% 
or > 120% [as calculated in Section 5.5.2]. 
The purpose of the PPS is to enable a supportive analysis of the DB part.  


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4.1.7 Modified Per-protocol analysis set 
The mPPS includes all subjects from the mFAS without protocol deviations that potentially 
affect the key secondary endpoint. Reasons for exclusion from the mPPS are: 
• DB-WD treatment duration less than 21 days. 
• Use of at least one medication as per protocol deviation list code 04A05 and 04A08 or 
use of additional diuretic or rescue medication in DB-WD part 3.  
• Compliance with DB-WD treatment < 80% or > 120% [as calculated in Section 5.5.2]. 
• Compliance with standardized background antihypertensive therapy in DB-WD part 
< 80% or > 120% [as calculated in Section 5.5.2]. 
The purpose of the mPPS is to enable a supportive analysis of the DB-WD part.  
4.1.8 Ambulatory blood pressure monitoring Full analysis set  
The aFAS includes all subjects from the FAS who have a baseline 24 h mean SBP, 
measured by ABPM with a total duration of at least 21 hours and at least 70% valid 
readings [Section 6.4.1]. Subjects will be evaluated according to their assigned study 
treatment in the DB part. 
4.1.9 Modified ambulatory blood pressure monitoring Full analysis set  
The maFAS includes all subjects from the mFAS who have a DB‑WD baseline 24 h mean 
SBP, measured by ABPM with a total duration of at least 21 hours and at least 70% valid 
readings [Section 6.4.1]. Subjects will be evaluated according to their assigned study 
treatment in the DB-WD part. 
4.1.10 Safety analysis set  
The SAF includes all randomized subjects who received at least one dose of study 
treatment in the DB part. Subjects will be evaluated according to the study treatment they 
received in the DB part. In the unlikely event that a subject received different treatments 
in the DB part, actual treatment will be set to the highest dose of aprocitentan that subject 
received (12.5 mg or 25 mg). 
4.1.11 Restricted Safety analysis set  
The subset of subjects from the SAF who received at least one dose of study treatment in 
the SB aprocitentan part will be referred to as the rSAF. 
4.1.12 Modified Safety analysis set  
The mSAF includes subjects from the SAF who received at least one dose of study 
treatment in the DB-WD part. Subjects will be evaluated according to the study treatment 
they received in the DB-WD part. In the unlikely event that a subject received different 
treatments in the DB-WD part, actual treatment will be set to be aprocitentan 25 mg. 


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4.1.13 Pharmacokinetic set 
The PK set includes all subjects from the SAF who received at least one dose of 
aprocitentan, had evaluable plasma concentrations and did not violate the protocol in a way 
that might affect the evaluation of the PK endpoint. 
Reasons for exclusion from the PK set are: 
• DB treatment duration less than 21 days. 
• Compliance with DB treatment < 80% or > 120% [as calculated in Section 5.5.2]. 
• AOBPM not done at trough at Week 4 (V6) as per protocol deviation list code 03F20. 
• PK samples not collected at Week 4 (V6) as per protocol deviation list code 03F26. 
4.2 Usage of the analysis sets 
The role of the analysis sets in each of the study parts (DB, SB aprocitentan and DB-WD) 
is summarized in Table 3. 
Table 3 
Role of the analysis sets 
Study part 
DB 
SB aprocitentan 
DB-WD 
Efficacy endpoints based on AOBPM 
FAS (PPS) 
– 
mFAS (mPPS) 
Efficacy endpoints based on ABPM 
aFAS 
– 
maFAS 
Safety endpoints 
SAF 
rSAF 
mSAF 
Pharmacokinetic endpoints 
PK  
– 
– 
ABPM = ambulatory blood pressure monitoring; aFAS = ABPM Full analysis set; AOBPM = automated office blood 
pressure measurement; DB = double-bind; FAS = Full analysis set; maFAS= modified ABPM Full analysis set; 
mFAS = modified Full analysis set; mPPS = modified Per-protocol set; mSAF = modified Safety analysis set; 
PK = pharmacokinetic; PPS = Per-protocol set; rSAF = restricted Safety set; SAF = Safety analysis set; 
SB = single‑blind; WD = withdrawal. 
 
Descriptive statistics for selected efficacy and safety endpoints during the RI period will 
be based on the RIS. The SCR will be used for subject listings. 


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5 
STUDY SUBJECT VARIABLES AND ANALYSES 
5.1 Subject disposition 
5.1.1 Study disposition  
A subject is considered: 
• Screened: if the subject has given informed consent to participate in the study and has 
received a subject number.  
− A screening failure is defined as a screened subject who did not enter the run-in. 
The reason for screening failure is collected in the Run-in Enrolment eCRF. 
Subjects who failed screening twice will only be counted once (and only the reason 
for the last screening failure will be tabulated). 
• To have entered the RI period: if the subject received at least one dose of RI treatment 
(placebo) according to the Study Treatment Log. 
− A run-in failure is defined as a subject in run-in who was not randomized. The 
reason for run-in failure is collected in the Randomization eCRF.  
• Randomized: if the subject was assigned a randomization number by the IRT system at 
Visit 4. 
− A DB drop-out is defined as a randomized subject who did not enter the SB 
aprocitentan part. 
• To have entered the SB aprocitentan part if the subject received at least one dose of SB 
aprocitentan according to the Study Treatment Log. 
− A SB aprocitentan drop-out is defined as subject in the SB aprocitentan part who 
was not re-randomized. The reason for not being re-randomized is collected in 
Re-Randomization eCRF.  
• Re-randomized: if the subject was assigned a re-randomization number by the IRT at 
Visit 11. 
− A DB-WD premature treatment discontinuation is defined as a re-randomized 
subject who did not complete study treatment.  
• To have completed study treatment: if on the Study Treatment Log Study period is 
‘Double-blind Withdrawal Treatment (Part 3)’ and Reason for treatment stop is 
‘Completion as per protocol’. 
• To have completed the study: when this is indicated on the End of Study Status eCRF. 
A disposition graph in the clinical study report will display the numbers of subjects in each 
category defined above. Subjects will be displayed according assigned study treatment, 


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where applicable. Any difference between assigned and actual treatment will be added in 
footnotes. 
The number (%) of screening failures (i.e., subjects screened but not in RI) will be 
calculated based on the SCR. Reasons for not being enrolled in the RI period as collected 
on the Enrollment eCRF will be tabulated for the SCR. All eligibility criteria not met 
during screening and run-in period and eligibility criteria not met grouped by category of 
inclusions/exclusions criteria and standardized background antihypertensive therapy status 
will be summarized on the SCR. 
The number (%) of RI failures (i.e., subjects in RI but not randomized) will be calculated 
based on the RIS. Reasons for not being randomized as collected on the Randomization 
eCRF (Part 1) will be tabulated for the RIS. 
The numbers of subjects randomized and re-randomized will be tabulated by treatment 
group for the FAS and mFAS, respectively. Reasons for not being re-randomized as 
collected on the Randomization eCRF (Part 3) will be tabulated for the FAS. 
The numbers of subjects screened, in run-in, randomized and re-randomized will also be 
provided by country and site. 
5.1.2 Study completion/discontinuation 
A subject is considered to have prematurely discontinued the study when this is indicated 
on the End of Study Status eCRF. Reasons for premature study discontinuation are 
collected on the same form and include: withdrawal by subject, AE, lost to FU, death, and 
other. If the reason for premature study discontinuation was related to the COVID-19 
pandemic, this was collected. 
Reasons for premature study discontinuation in the RI period will be summarized based on 
the RIS. Reasons for premature study discontinuation in the randomized treatment period 
will be summarized for the RND. Reasons related to the COVID-19 pandemic will be 
included in these summaries and will also be listed as such. 
5.1.3 Study treatment completion/discontinuation 
A subject is considered to have prematurely discontinued treatment in the RI period if on 
the Study Treatment Log the ‘Study period’ is ‘Single-Blind Run-in’ and ‘Reason for 
treatment stop’ is ‘Discontinued’.  
A subject is considered to have prematurely discontinued study treatment in the DB (SB 
aprocitentan, DB-WD, respectively) part if on the Study Treatment Log the ‘Reason for 
treatment stop’ is ‘Discontinued’ for the corresponding ‘Study period’.  
Reasons for premature discontinuation are collected on the same form and include: AE, 
lack of efficacy, withdrawal by subject, lost to FU, death, pregnancy, and other. If the 


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reason for premature study treatment discontinuation was related to the COVID-19 
pandemic, this was collected. 
The numbers of subjects treated in the DB, SB aprocitentan and DB-WD parts will be 
tabulated by treatment group in the SAF, rSAF and mSAF, respectively. 
The number (%) of subjects with and the reasons for premature treatment discontinuation 
in the RI period will be summarized based on the RIS.  
The number (%) of subjects with and the reasons for premature treatment discontinuation 
in the randomized treatment period will be summarized by study part and treatment group 
(within study part) in the SAF, rSAF or mSAF, where appropriate. Reasons for premature 
study treatment discontinuation related to COVID-19 pandemic will also be summarized. 
5.2 Protocol deviations 
The number (%) of subjects with all PDs and important PDs (as per PD code list) will be 
summarized by treatment group and by study part DB+SB and DB-WD based on the FAS 
(for DB+SB) and based on the mFAS (for DB-WD). In addition, the same summaries of 
all PDs and important PDs will be provided separately for PDs related to the COVID-19 
pandemic as per FDA guidance.  
5.3 Exclusion from analysis data sets 
The number (%) of subjects excluded from the PPS and the reasons for exclusion 
[Section 4.1.6] will be tabulated by treatment group based on the FAS. The number (%) of 
subjects excluded from the mPPS the reasons for exclusion [Section 4.1.7] will be tabulated 
by treatment group based on the mFAS. 
The number (%) of subjects excluded from the PK set and reasons for exclusion will be 
tabulated by treatment group based on the SAF. 
5.4 Subject characteristics 
Subject characteristics are obtained at Screening (i.e., Visit 1). If a subject was re-screened 
and a value changed between Screening and Re-screening, the value at Re-screening should 
be used.  
5.4.1 Demographics 
Demographic variables include age, sex, race and ethnicity as collected at Screening on the 
Demographics eCRF form as well as country and region.  
Age will also be categorized as 18–< 65, 65–< 75 and  ≥ 75 years.  
Country will be derived from site number. 


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Region is provisionally defined as:  
• Asia/Australia (Australia, China, South Korea),  
• Europe (Belgium, Czech Republic, Denmark, Finland, France, Germany, Italy, 
Hungary, Lithuania, Netherlands, Poland, Russia, Spain, Ukraine, United Kingdom, 
Israel and Greece), and  
• North America (Canada, US).  
Each of these three regions has at least 50 subjects [section 2.2.5 of ICH 2017a].  
Other demographic variables include: 
• Height and body weight (converted into cm and kg, respectively, if applicable)  
• Body weight at baseline will also be categorized as ≤ 100 kg, >100 kg 
• BMI at screening where BMI = weight[kg]/(height[cm]/100)2 
• BMI at screening will also be categorized as < 25, 25– <30, 30– <40 and ≥40 kg/m2  
Demographic variables will be summarized by treatment group as well as overall in the 
DB and DB-WD periods for the FAS and mFAS, respectively. For European Clinical Trials 
Database (EudraCT) purposes, the number of subjects treated in each age category (< 18, 
18– <65, 65–<85 and ≥ 85 years at Screening) will be summarized for the FAS and mFAS. 
5.4.2 Disease characteristics 
Disease characteristics include: 
• Time from first diagnosis of hypertension [years] = (date of Visit 1 – date of 
diagnosis)/365.25 (from the Hypertension History eCRF) at Screening. 
• Number of antihypertensive therapies present at screening [as defined in Section 5.4.4]; 
<3, 3, 4 and ≥5  
• SiSBP and sitting diastolic BP (SiDBP) as measured by AOBPM at screening  
• UACR; < 30 mg/g, 30–300 mg/g, > 300 mg/g at Baseline. 
• (eGFR; < 30, 30–< 45, 45–< 60, ≥ 60 mL/min/1.73 m2) according to the CKD-EPI 
equation [Levey 2009] at Baseline. 
Disease characteristics will be summarized by treatment group as well as overall in the DB 
and DB-WD periods for the FAS and mFAS, respectively. 
5.4.3 Medical history 
Medical history collected at Screening will be coded using MedDRA. Previous 
diseases/procedures are medical history where ‘Ongoing at informed consent signed’ is 
‘No’ on the Medical History eCRF. Ongoing diseases/procedures are medical history 


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where ‘Ongoing at informed consent signed’ is ‘Yes’. If the response to ‘Ongoing at 
Informed consent’ is missing, then the disease/procedure is considered as ongoing. 
Medical history will be summarized by SOC, PT and treatment group as well as overall in 
the FAS. This will be done separately for previous and ongoing diseases/ procedures. 
5.4.4 Previous and concomitant therapies 
Therapies are collected in the Previous/Concomitant Medications eCRF, and terms are 
coded using the WHO Drug code dictionary and the ATC class code using the versions 
available at database lock.  
Previous therapy is medication for which the end date is prior to the date of first 
randomization. If the end date is (partially) missing, the imputation rules from 
Section 10.2.2 will be applied.  
Concomitant therapy is any medication that is ongoing at Randomization or initiated during 
the randomized treatment period. In particular:  
• DB study treatment concomitant therapies are treatments that are either ongoing at the 
start of DB study treatment or initiated during the DB treatment part. 
SB study treatment concomitant therapies and DB-WD study treatment concomitant 
therapies are defined similarly. Rules for handling (partially) missing dates are detailed in 
Section 10.2.2. 
A study-concomitant therapy is medication that is ongoing at or initiated after signing of 
informed consent or initiated up to 30 days after EOT. 
The number (%) of subjects having taken at least one concomitant medication will be 
summarized by ATC classification level 4 and individual preferred name within each ATC 
classification by study part. Concomitant therapy will be sorted by ATC class and preferred 
name within each ATC class by descending frequency based on all treatment groups 
combined. 
All study-concomitant medication will be listed, where ‘treatment’-concomitant 
medication will be flagged. 
Individual antihypertensive therapies stopped or ongoing during screening period by ATC 
classifications will be summarized based on the FAS. The following categories will be 
shown in the table:  
• Renin-angiotensin system blockers divided in 2 categories:  
− Angiotensin-converting enzyme inhibitor (ACEi).   
− Angiotensin receptor blockers (ARB). 


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• Calcium channel blockers (CCB). 
• Diuretics 
− Mineralocorticoid receptor antagonist (MRA). 
• Beta-blockers. 
• Centrally acting antihypertensives. 
• Others in combination [as defined in Appendix 14.4]. 
• Others.  
5.5 Study treatment duration and compliance 
5.5.1 Treatment duration 
Randomized treatment duration (in days) is defined separately for the DB, SB aprocitentan 
and DB-WD parts as the date of the last dose of treatment in the DB (SB aprocitentan, 
DB-WD, respectively) part minus the date of the first dose in the DB (SB aprocitentan, 
DB-WD, respectively) part plus one day, ignoring treatment interruptions. The detailed 
derivations based on the Study Treatment Log are given in Section 10.1.1. Randomized 
treatment duration will also be expressed in weeks.  
RI treatment duration is defined as the date of the last dose of SB placebo minus the date 
of the first dose of SB placebo plus one day [see Section 10.1.1]. 
Standardized background antihypertensive therapy duration in the RI period as well as in 
the DB, SB aprocitentan, and DB-WD parts is defined similarly based on the Standardized 
Background Antihypertensive Therapy Log. 
Treatment duration (in days as well as weeks) will be summarized by study part and 
treatment group (within study part) in the SAF, rSAF and mSAF, respectively. Total 
exposure (in subject-years, where a year equals 365.25 days) will also be summarized by 
study part and treatment group.  
Time from first dose of DB treatment to (premature) treatment discontinuation in the DB 
or SB aprocitentan part will be summarized by treatment group using Kaplan-Meier plots 
(supplemented with a table displaying the numbers of subjects at risk, with an event, and 
censored by treatment group, using weekly intervals) in the SAF. For subjects who 
completed the treatment, time to discontinuation will be censored at the last dose of SB 
treatment (or at the last dose of DB treatment if the subject did not enter the SB part). 
Additionally, a ‘two-step’ Cox model with a factor for treatment in the DB part will be 
fitted. This model allows for different treatment effects in the DB and SB aprocitentan parts. 
The treatment effect in the latter part (if any) is expected to be smaller than in the former 
part [for details, see Section 8.2]. 


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Time from first dose of DB-WD treatment to (premature) treatment discontinuation in the 
DB-WD part will be summarized similarly in the mSAF, except that the Cox model is the 
conventional one. 
RI treatment duration will be summarized based on the RIS. Standardized background 
antihypertensive therapy duration will be summarized by study part and treatment group 
(within study part) in the SAF, rSAF and mSAF, respectively. 
5.5.2 Compliance with study treatment 
Randomized treatment compliance is defined separately for the DB, SB aprocitentan and 
DB-WD parts as: 
Compliance = [(number of tablets dispensed − number of tablets returned*) / 
treatment duration [days]. 
* If a subject did not return his/her bottle (e.g., the bottle is lost), the compliance will not 
be calculated and the compliance for the parts will be set to missing. The bottle is allocated 
to the study part in which it was dispensed.  
Here the number of tablets is calculated separately for the DB (SB aprocitentan, DB-WD, 
respectively) part based on the Study Treatment Dispensing & Accountability eCRF and 
the DB (SB aprocitentan, DB-WD, respectively) treatment duration is defined as in 
Section 5.5.1. 
RI treatment compliance is defined as the number of tablets taken during the RI period 
according to the Study Treatment Dispensing & Accountability eCRF, divided by the 
RI treatment duration (in days) defined in Section 5.5.1.  
Standardized background antihypertensive therapy compliance is defined similarly based 
on the Standardized Background Antihypertensive Therapy Dispensing & 
Accountability eCRF. 
Randomized treatment compliance will be summarized by study part and treatment group 
(within study part) in the SAF, rSAF and mSAF, respectively. RI treatment compliance 
will summarized be based on the RIS.  
Compliance to the standardized antihypertensive background therapy will be summarized 
by study part and treatment group (within study part) in the SAF, rSAF and mSAF, 
respectively.  
Adherence (Y/N) to the standardized background antihypertensive therapy (as measured 
by urinalysis for valsartan) will be summarized by study part, visit and treatment group 
(both within study part) in the SAF, rSAF and mSAF, respectively. 


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A subject is considered to have interrupted study treatment or standardized background 
antihypertensive therapy if on the Study Treatment Log or Background Therapy Log 
the ‘Reason for treatment stop’ is ‘Interruption due to an AE’ or ‘Interruption not due to 
an AE’.  
Reasons for study treatment interruption will be summarized by study part and treatment 
group (within study part) in the SAF, rSAF or mSAF, where appropriate. 
6 
EFFICACY VARIABLES AND ANALYSES 
6.1 Overall testing strategy 
Three null hypotheses will be tested in this study. The first two null hypotheses (H10 and 
H20) will be tested in parallel using the Bonferroni correction. The third null hypothesis 
(H30) will only be tested if H10 or H20 is rejected. 
The first null hypothesis H10 is that there is no difference between aprocitentan 25 mg and 
placebo in the DB part in the mean change from baseline to Week 4 in mean trough SiSBP. 
The alternative hypothesis H1a is that there is a difference between these groups: 
H10: μ1 = μ0 
vs 
H1a: μ1 ≠ μ0. 
Here μ0 and μ1 denote the mean change from baseline to Week 4 in mean trough SiSBP in 
the placebo and aprocitentan 25 mg groups, respectively. This hypothesis will be tested at 
a two-sided significance level of 0.025. 
The second null hypothesis H20 is that there is no difference between aprocitentan 12.5 mg 
and placebo in the DB part in the mean change from baseline to Week 4 in mean trough 
SiSBP. The alternative hypothesis H2a is that there is a difference between these groups: 
H20: μ2 = μ0 
vs 
H2a: μ2 ≠ μ0. 
Here μ0 and μ2 denote the mean change from baseline to Week 4 in mean trough SiSBP in 
the placebo and aprocitentan 12.5 mg groups, respectively. This hypothesis will be tested 
at a two-sided significance level of 0.025. 
The third null hypothesis H30 is that there is no difference between aprocitentan 25 mg and 
placebo in the DB-WD part in the mean change from DB-WD baseline (Week 36) to 
Week 40 in mean trough SiSBP. The alternative hypothesis H3a is that there is a difference 
between these groups: 
H30: ν1 = ν0 
vs 
H3a: ν1 ≠ ν0. 
Here ν0 and ν1 denote the mean change from DB-WD baseline (Week 36) to Week 40 in 
mean trough SiSBP in the placebo and aprocitentan 25 mg groups, respectively. This 
hypothesis will only be tested if H10 or H20 is rejected: at a two-sided significance level of 


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0.05 if both H10 and H20 have been rejected and at a two-sided significance level of 0.025 
if only one of H10 and H20 has been rejected. The overall type I error is protected at 0.05 
[Bretz 2009].  
The testing strategy is summarized in Figure 2. 
Figure 2 
Testing strategy 
 
The ‘1’ next to the arrows indicates that if H10 (H20) is rejected the associated alpha of 0.025 will be propagated to test H30. 
 
6.2 Primary endpoint analysis 
6.2.1 Variable 
The primary efficacy endpoint is the change from baseline to Week 4 of DB treatment in 
mean trough SiSBP measured by AOBPM. 
Here ‘mean trough’ denotes the average of four AOBPM readings (from a Microlife® 
WatchBP Office device performing five readings; the first is excluded from the average 
which will be in the vendor’s data transfer) taken at trough (i.e., before the morning intake 
of study treatment and standardized background antihypertensive therapy). 
6.2.2 Intercurrent events and choice of estimand 
There are two types of intercurrent events that may interfere with the analysis of the 
primary endpoint: premature discontinuation of DB treatment or the addition / dose 
increase of a diuretic. Use of rescue medication, although not allowed during the DB part, 
will be also considered as an intercurrent event.  
All AOBPM measurements, irrespective of any intercurrent event(s), will be included in 
the main analysis, leading to a treatment policy strategy estimand in ICH terminology 
[ICH 2017b]. 


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Based on the Phase 2 study in essential hypertension, AC-080A201, it is expected that 5% 
of subjects in the FAS will have a missing Week 4 AOBPM, mainly due to premature 
treatment discontinuation. In the main analysis [Section 6.2.3] missing data will not be 
imputed but will be handled by a mixed model assuming that the data are MAR. Sensitivity 
analyses will be performed, investigating the impact of deviations from MAR as well as 
considering a different estimand [Section 6.2.4]. 
6.2.3 Main analysis for the primary endpoint 
The main analysis of the change from baseline to Week 4 (i.e., in the DB part) in mean 
trough SiSBP measured by AOBPM will be conducted on the FAS. The treatment groups 
in this analysis are aprocitentan 25 mg, aprocitentan 12.5 mg, and placebo. The first and 
second null hypotheses (H10 and H20) will be tested as described in Section 6.1. 
Changes from baseline to post-baseline visits up to Week 4 in mean trough SiSBP will be 
analyzed using a mixed model with factors for treatment group, visit and treatment by visit 
interaction, and covariates for baseline SiSBP and the interaction between baseline SiSBP 
and visit. An unstructured covariance matrix will be used to account for the correlation 
between repeated BP measurements from the same subject.  
LSM differences vs placebo at Week 4 and their 97.5% CIs will be obtained from the model. 
The associated p-values will be used to test the first and second null hypotheses.  
6.2.4 Sensitivity analyses for the primary endpoint 
The impact of deviations from the MAR assumption underlying the mixed model will be 
investigated in sensitivity analyses assuming that in the aprocitentan groups the data are 
MNAR [Mallinckrodt 2013].  
Two control-based MI procedures will be performed under MNAR: a CR and a J2R 
approach [Carpenter 2013]. In addition, a tipping point approach will be used to assess how 
severe departures from the MAR assumption must be to overturn the conclusions of the 
main analysis. For details, see Section 8.2.  
In another sensitivity analysis on the FAS, AOBPM measurements obtained more than one 
day1 after premature discontinuation of DB treatment will be excluded from the main 
analysis (i.e., considered as missing), leading to a hypothetical strategy estimand in ICH 
terminology [ICH 2017b]. This approach reflects the anticipation that the effect of a 
treatment on BP will be lost quickly after the treatment has been discontinued. In this 
setting, it is not the usual practice to assess effectiveness after (premature) treatment 
discontinuation [O’Neill 2012]. In addition, AOBPM measurements taken after the 
                                                 
1 If the last dose of DB treatment is taken at study Day x then an AOBPM measurement taken at Day x + 1 will be 
included in the analysis, but a measurement taken at Day x + 2 will not. 


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addition of a diuretic or use of rescue medication that also has an impact on BP will be 
excluded from the analysis. 
Finally, the primary analysis will be performed excluding site 4204 from which the data 
are considered not trustworthy (as per internal audit report).  
6.2.5 Supportive analyses for the primary endpoint 
As a supportive analysis, the mixed model (as specified for the main analysis) will be 
performed on the PPS. An ANCOVA will be performed on the FAS for the change from 
baseline to Week 4 imputing missing data using LOCF and, separately, using BOCF. 
In LOCF a missing post-baseline value will be replaced by the preceding value (except the 
baseline value; so, the analysis will be restricted to subjects with a post-baseline value). In 
BOCF, a missing post-baseline value will be replaced by the baseline (so, the change will 
be zero). 
6.2.6 Subgroup analyses for the primary endpoint 
The following subgroups will be considered. 
• Age at screening (18–< 65, 65–< 75 and ≥ 75 years). 
• Sex (male/female). 
• Weight at baseline (≤ 100 kg, > 100 kg). 
• BMI at screening < 30, 30–< 40 and ≥ 40 kg/m2. 
• Race (Black or African American, White, Asian, Other*). 
• Region (Asia/Australia, Europe, North America, as defined in Section 5.4.1). 
• UACR at Baseline (< 30 mg/g, 30–300 mg/g, > 300 mg/g., 
• CKD stage at baseline (1–2 defined as eGFR ≥ 60 mL/min1.73 m2, 3–4 defined as 
eGFR 15 to < 60 mL/min/1.73 m2). 
• Diabetes as per medical history (Y/N) (defined as Hyperglycaemia/new onset 
diabetes mellitus [SMQ]). 
• Protocol Version 1/2 vs protocol Version 3 at randomization. Note: in protocol 
Version 3, beta-blockers were counted as antihypertensive medications at Screening, 
which was not the case in Version 1/2. 
* The ‘Other’ category will not be considered for subgroup analyses due to the mix of races and small number of subjects 
limiting the ability (i.e., low power) to detect differences between treatment groups. ‘Other’ includes American Indian or 
Alaska Native, Native Hawaiian or other Pacific Islander and Other. 
If the size of a subgroup is lower than 25 subjects, subgroup categories might be pooled. 


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The aim of the subgroup analyses is to explore the consistency of treatment effect in 
relevant subgroups. Results of the subgroup analyses will be displayed in a forest plot and 
will include: 
• An estimate of the treatment effect for each aprocitentan dose vs placebo with its 
95% CI for each level of the subgroup. It will be calculated as the LSM difference vs 
placebo at Week 4 obtained separately for each subgroup level as described for the 
main analysis [Section 6.2.3] but using 95% rather than 97.5% CIs. 
• A p-value for the interaction test obtained from the mixed model for the main analysis 
extended with factors for the subgroup, treatment by subgroup interaction and treatment 
by subgroup by visit interaction, with appropriate contrasts. 
• A vertical reference line displayed at the level of the overall treatment effect. 
The study is not designed or powered to detect interactions but an arbitrary two-sided 
significance level of 0.10 will be used for the interpretation of the interaction test. No 
multiplicity adjustment is applied as these subgroup analyses are exploratory in nature. 
The analyses of the primary endpoint are summarized in Table 4. 
6.2.7 Impact of the COVID-19 pandemic on the analysis of primary endpoint 
The analysis of the primary endpoint is based on AOBPM data collected at randomization 
(Visit 4) and Week 4 (Visit 6). Missing data because of missed on-site Visit 4 and Visit 6 
due to the COVID-19 pandemic will not be imputed but will be handled by the mixed 
model specified for the primary endpoint analysis.  
If Visit 4 and/or Visit 6 was performed off-site and AOBPM could not be performed, HBP 
was to be measured instead. These values will be summarized using descriptive statistics 
[D‑20.063] and will not be used for the analysis of primary endpoint.  
6.3 Key secondary endpoint analysis 
6.3.1 Variable 
The key secondary efficacy endpoint is the change from DB-WD baseline (Week 36) to 
Week 40 in mean trough SiSBP measured by AOBPM. 
6.3.2 Intercurrent events and choice of estimand 
There are three types of intercurrent events that may interfere with the analysis of the key 
secondary endpoint: premature discontinuation of DB-WD treatment, initiation of 
antihypertensive rescue medication (in the DB-WD part) or the addition / dose increase of 
a diuretic (in the DB-WD part).  
All AOBPM measurements, irrespective of any intercurrent event(s), will be included in 
the analysis, leading to a treatment policy strategy estimand in ICH terminology 
[ICH 2017b].  


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It is expected that 10% of subjects in the mFAS will have a missing Week 40 AOBPM. In 
the main analysis [Section 6.3.3] missing data will not be imputed but will be handled by 
a mixed model assuming that the missing data are MAR. Sensitivity analyses will be 
performed, investigating the impact of deviations from MAR as well as considering a 
different estimand [Section 6.3.4]. 
6.3.3 Main analysis for the key secondary endpoint 
The main analysis for the change from DB-WD baseline (Week 36) to Week 40 (i.e., in 
the DB-WD part) in mean trough SiSBP measured by AOBPM will be conducted on the 
mFAS. The treatment groups in this analysis are aprocitentan 25 mg and placebo. The 
analyses will be adjusted for the stratum at Re‑randomization (i.e., randomized treatment 
in the DB part). The third null hypothesis (H30) will be tested as described in Section 6.1. 
Changes from DB-WD baseline (Week 36) to visits up to Week 40 in mean trough SiSBP 
will be analyzed using a mixed model with factors for stratum (i.e., randomized treatment 
in the DB part), treatment group, visit, and treatment by visit interaction and covariates for 
DB-WD baseline (Week 36) SiSBP and the interaction between DB-WD baseline 
(Week 36) SiSBP and visit and an unstructured covariance matrix.  
LSM differences vs placebo for the change from DB-WD baseline (Week 36) to Week 40 
and their 95% CIs will be obtained from the model. The associated p-values will be used 
to test the third null hypothesis. 
6.3.4 Sensitivity analyses for the key secondary endpoint 
The impact of deviations from the MAR assumption underlying the mixed model will be 
investigated in sensitivity analyses under MNAR as described in Section 6.2.4 and detailed 
in Section 8.2. 
In another sensitivity analysis on the mFAS, all AOBPM measurements obtained more 
than one day after premature discontinuation of DB-WD treatment will be excluded from 
the main analysis. In addition, the initiation of antihypertensive rescue medication could 
influence the BP of a subject [O’Neill 2012]. For this reason, AOBPM measurements 
obtained after initiation of antihypertensive rescue medication in the DB-WD part will also 
be excluded from this analysis (i.e., considered as missing), leading to a hypothetical 
strategy estimand in ICH terminology [ICH 2017b]. Finally, AOBPM measurements taken 
after the addition of a diuretic (but also having an impact on BP) will be excluded from the 
analysis. (Note: antihypertensive rescue medication or a diuretic initiated in the SB 
aprocitentan part that is continued unchanged in the DB-WD part will not lead to exclusion 
from analysis). 
Finally, the main analysis for the key secondary endpoint will be performed excluding 
site 4204 from which the data are considered not trustworthy (as per internal audit report).  


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6.3.5 Supportive analyses for the key secondary endpoint 
As supportive analyses, the mixed model (as specified for the main analysis) will be 
performed in the mPPS and ANCOVAs will be performed on the mFAS for the change 
from DB-WD baseline (Week 36) to Week 40 imputing missing data using LOCF and 
BOCF, respectively. 
6.3.6 Subgroup analyses for the key secondary endpoint 
Subgroup analyses in the DB-WD part will be performed as described for the DB part but 
only for age, sex, race and region [as defined in Section 6.2.6]. In addition, a subgroup 
analysis based on the SiSBP at DB-WD baseline (< 135 mmHg vs ≥ 135 mmHg) will be 
performed. Subjects without antihypertensive rescue medication are considered an 
enriched sub-population of the mFAS. 
The analyses of the key secondary endpoint are summarized in Table 4. 
6.3.7 Impact of the COVID-19 pandemic on the analysis of key secondary 
endpoint 
The analysis of the key secondary endpoint is based on AOBPM data collected at 
re‑randomization (Visit 11) and Week 40 (Visit 13). Missing data because of missed on‑site 
Visit 11 and Visit 13 due to the COVID-19 pandemic will be handled by the mixed model 
specified for the key secondary endpoint analysis. 
If Visit 11 and/or Visit 13 was performed off-site and AOBPM could not be performed, 
HBP was to be measured instead. These values will be summarized using descriptive 
statistics and will not be used for the analysis of the key secondary endpoint [D‑20.063].  
6.4 Other secondary efficacy endpoints analyses 
6.4.1 Variables 
The other secondary efficacy endpoints are: 
• Change from baseline to Week 4 of DB treatment in mean trough SiDBP measured by 
AOBPM. 
• Changes from baseline to Week 4 of DB treatment in 24 h mean systolic BP (SBP) and 
diastolic BP (DBP) measured by 24 h ABPM. 
− At each visit the 24 h mean SBP (or DBP) is derived from the area under the 
SBP-time (or DBP-time) curve, divided by the time span. The area under the curve 
is calculated by the trapezoidal rule. Time points later than 24 hours after the first 
time point will be excluded from the calculation. The change from baseline to 
Week 4 will be obtained by subtraction. 
• Change from DB-WD baseline (Week 36) to Week 40 of DB-WD treatment in mean 
trough SiDBP measured by AOBPM. 


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• Changes from DB-WD baseline (Week 36) to Week 40 of DB-WD treatment in 24 h 
mean SBP and DBP measured by 24 h ABPM.  
− These are derived similarly to changes from baseline to Week 4 of DB treatment in 
24 h mean SBP and DBP, with baseline and Week 4 replaced by DB-WD baseline 
(Week 36) and Week 40, respectively. 
Each 24 h ABPM reading is supplemented by six quality criteria (provided by the vendor): 
1. Start time must be between 06:00 and 12:00 
2. Minimum duration of 24 hours after beginning of test 
3. Minimum of 70% valid readings in the period 
4. Total Required Hours is at least 21 
5. Total Exception Hours is at most 3 
6. Total Consecutive Exception Hours is 0 
The main evaluation of ABPM data will be performed based on ABPMs with at least 70% 
valid readings and a total duration of at least 21 hours. In the calculation of the percentage, 
ABPM measurements performed during the first ten minutes will be counted as a single 
measurement to account for the manual measurements performed by the subject in testing 
the device. A supportive evaluation will be based on ABPM readings that satisfy all six 
criteria mentioned above. 
6.4.2 Analyses 
All other secondary efficacy variables will be tested at the two-sided significance level 
of 0.05. No correction for multiplicity will be applied. 
• Change from baseline to Week 4 of DB treatment in mean trough SiDBP measured by 
AOBPM will be analyzed in the FAS using the same mixed model as specified for 
SiSBP (main analysis) in the DB part.  
• Changes from baseline to Week 4 of DB treatment in 24 h mean SBP and DBP 
measured by ABPM will be analyzed in the aFAS using an ANCOVA with a factor for 
treatment group and a covariate for baseline 24 h mean SBP (or DBP).  
• Change from DB-WD baseline (Week 36) to Week 40 of DB-WD treatment in mean 
trough SiDBP as measured by AOBPM will be analyzed in the mFAS using the same 
mixed model as specified for SiSBP (main analysis) in the DB-WD part.  
• Changes from DB-WD baseline (Week 36) to Week 40 of DB-WD treatment in 24 h 
mean SBP and DBP as measured by ABPM will be analyzed in the maFAS using the 
same ANCOVA as described for changes from baseline to Week 4 of DB treatment in 
24 h mean SBP and DBP, but with baseline replaced by DB-WD baseline (Week 36). 


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The analyses of the other secondary endpoints are summarized in Table 4. 
6.5 Other efficacy endpoints 
6.5.1 Variables 
• Changes from baseline to Week 2 of DB treatment in mean trough SiSBP and SiDBP 
measured by AOBPM. 
• Changes from baseline to Week 4 in daytime and nighttime mean SBP and DBP 
measured by 24 h ABPM: 
− Daytime is defined as between 09:00 and 21:00.  
− Nighttime is defined as between 01:00 and 06:00 [O’Brien 2013]. 
• Changes from DB-WD baseline (Week 36) to Week 38, Week 44 and Week 48 of 
DB‑WD treatment in mean trough SiSBP and SiDBP measured by AOBPM. 
• Changes from DB-WD baseline (Week 36) to Week 40 in daytime and nighttime mean 
SBP and DBP measured by 24 h ABPM. 
• Ratios to baseline for all assessed time points in the DB and SB aprocitentan parts and 
to DB-WD baseline (Week 36) for all assessed time points in the DB-WD part in 
UACR. 
• Discontinuation of randomized study treatment due to lack of efficacy (as collected on 
the Study Treatment Log) by study part (DB, SB aprocitentan and DB-WD). 
• Initiation 
of 
antihypertensive 
rescue 
medication 
(as 
indicated 
on 
the 
Previous/Concomitant Medication eCRF) in the SB aprocitentan part or DB‑WD part. 
(Rescue medication is not allowed in the DB part). 
• Observed values of home SBP/DBP by visit collected due to the COVID-19 pandemic 
in the DB, SB aprocitentan, and DB-WD parts. 
The following endpoints related to BP control and response were added as compared to the 
protocol [refer to Section 11]: 
• Binary control variables will be created at each visit for SiSBP and SiDBP measured 
by AOBPM: 
− SBP Control = ‘Yes’ if patient achieved a mean trough SiSBP of < 135 mmHg or 
< 140 mmHg at the visit. SBP Control= ‘No’ otherwise.  
− DBP Control = ‘Yes’ if patient achieved a mean trough SiDBP of < 85 mmHg or 
< 90 mmHg at the visit. DBP Control= ‘No’ otherwise.  
− SBP/DBP control  = ‘Yes’ if patient achieved a mean trough SiSBP of < 135 mmHg 
and SiDBP of < 85 mmHg or SiSBP of < 140 and SiDBP of < 90 mmHg at the 
visit. SBP/DBP control = ‘No’ otherwise.  


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• Binary response variable will be created at each visit in the DB and SB parts of the 
study for SiSBP and SiDBP measured by AOBPM: 
− SBP Response = ‘Yes’ if patient achieved a reduction in SiSBP from baseline of 
≥ 10 mmHg or ≥ 15 mmHg in the DB and SB aprocitentan parts. SBP Response = 
‘No’ otherwise.  
− DBP Response = ‘Yes’ if patient achieved a reduction in SiDBP from baseline of 
≥ 5 mmHg or ≥ 10 mmHg in the DB and SB aprocitentan parts. DBP Response = 
‘No’ otherwise.  
− SBP/DBP Response = ‘Yes’ if patient achieved a reduction in SiSBP from baseline 
of ≥ 10 mmHg and SiDBP of ≥ 5 mmHg or achieved a reduction in SiSBP from 
baseline ≥ 15 mmHg and SiDBP of ≥ 10 mmHg at the visit. SBP/DBP response = 
‘No’ otherwise.  
• A binary response variable will also be created for each visit in the DB-WD part (in 
which a blood pressure increase may occur) 
− SBP Withdrawal Response = ‘Yes’ if patient achieved an increase in SiSBP from 
DB-WD baseline of ≥ 5 mmHg or ≥ 10 mmHg in the DB-WD part. SBP 
Withdrawal Response = ‘No’ otherwise.  
− DBP Withdrawal Response = ‘Yes’ if patient achieved an increase in SiDBP from 
DB-WD baseline of ≥ 3 mmHg or ≥ 6 mmHg in the DB-WD part. DBP Withdrawal 
Response = ‘No’ otherwise. 
− SBP/DBP Withdrawal Response = ‘Yes’ if patient achieved an increase in SiSBP 
from DB-WD baseline of ≥ 5 mmHg and SiDBP of ≥ 3 mmHg or an increase in 
SiSBP from DB-WD baseline of ≥ 10 mmHg and SiDBP of ≥ 6 mmHg. SBP/DBP 
Withdrawal response = ‘No’ otherwise.  
6.5.2 Analyses 
All other efficacy variables will be tested at the two-sided significance level of 0.05. No 
correction for multiplicity will be applied. 
• Changes from baseline to Week 2 of DB treatment in mean trough SiSBP and SiDBP 
measured by AOBPM will be analyzed using the mixed model described for changes 
from baseline to Week 4 in mean trough SiSBP and SiDBP, respectively. 
• Changes from baseline to Week 4 in daytime and nighttime mean SBP and DBP 
measured by ABPM will be analyzed in the aFAS using the same ANCOVA as 
described for 24 h mean SBP and DBP. 
• Changes from DB-WD baseline (Week 36) to Week 38 of DB-WD treatment in mean 
trough SiSBP and SiDBP measured by AOBPM will be analyzed in the mFAS using 
the mixed model described for changes from DB-WD baseline (Week 36) to Week 40 
in mean trough SiSBP and SiDBP, respectively. 


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− Changes from DB-WD baseline (Week 36) to Weeks 40 and 48 of DB-WD treatment 
in mean trough SiSBP/SiDBP measured by AOBPM will be analyzed in the mFAS 
using the same mixed model, extended with Week 44 and Week 48. 
• Changes from DB-WD baseline (Week 36) to Week 40 in daytime and nighttime mean 
SBP and DBP measured by ABPM will be analyzed in the maFAS using the same 
ANCOVA as described for 24 h mean. 
• Ratios to baseline (and DB-WD baseline [Week 36] as applicable) for all assessed time 
points of DB+SB and DB-WD parts in UACR will be log transformed and analyzed 
using a mixed model with a factor for treatment group, visit, treatment by visit 
interaction, covariates for baseline (DB-WD baseline [Week 36]) log UACR and visit 
by baseline (DB-WD baseline [Week 36]) interaction and an unstructured covariance 
matrix. This will be done separately for the DB+SB part on the FAS and for the 
DB‑WD part on the mFAS. 
• The number (%) of subjects who discontinued study treatment due to lack of efficacy 
will be tabulated by study part (DB, SB aprocitentan and DB-WD) and treatment group 
(within study part) in the FAS (2×) and mFAS, respectively. If there are at least 
12 subjects discontinued due to lack of efficacy, time from Randomization to treatment 
discontinuation due to lack of efficacy in the DB or SB aprocitentan part will be 
summarized by treatment group using Kaplan-Meier plots in the FAS. For subjects who 
did not discontinue treatment or discontinued treatment for reasons other than lack of 
efficacy, time to discontinuation will be censored at the last dose of DB or SB treatment 
(whichever comes last). Additionally, a ‘two-step’ Cox model with a factor for 
treatment will be fitted [see Section 8.2 for details]. Time from Re-randomization to 
treatment discontinuation due to lack of efficacy in the DB-WD part will be 
summarized similarly in the mSAF, except that the Cox model is the conventional one. 
For subjects who did not discontinue treatment or discontinued treatment for reasons 
other than lack of efficacy in the DB-WD part, time to discontinuation will be censored 
at the last DB-WD treatment + 30 days (or EOS date, whichever comes first). 
• The number (%) of subjects who initiated antihypertensive rescue medication will be 
summarized by study part (SB and DB-WD; rescue medication is not allowed in the 
DB part) and treatment group (within study part).  
• Home SBP/DBP collected due to the COVID-19 pandemic will be summarized by visit 
in DB, SB and DB-WD parts using descriptive statistics. 
• The number (%) of subjects with SBP/DBP Control will be tabulated for the DB+SB 
and DB-WD parts at each visit by treatment group in the FAS and mFAS, respectively. 
Subjects with a missing value at a given visit will be excluded from the analysis at that 
visit. The Cochran-Mantel-Haenszel (CMH) test will be used to test for a difference in 
the Control proportions at Week 4 between treatment groups in DB part on the FAS 
and at Week 40 between treatment groups in DB-WD part (stratified by randomized 


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treatment in the DB part) on the mFAS. The treatment effect will be expressed in terms 
of the aprocitentan to placebo OR and corresponding 95% CI. An OR > 1 will indicate 
a benefit of aprocitentan as compared to placebo. 
• The number (%) of subjects with SBP/DBP Response will be tabulated for the DB+SB 
and DB-WD parts at each visit by treatment group in the FAS and mFAS, respectively. 
Similar analyses as for control will be done at Week 4 and Week 40.  
The analyses of the other endpoints are summarized in Table 4. 
6.6 Overview of efficacy analyses  
The efficacy analyses are summarized in Table 4. 
Each analysis will be accompanied by a summary table with the descriptive statistics.  


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Table 4 
Summary of efficacy analyses 
Endpoint 
Measured 
by 
Analysis 
Model 
Analysis 
set 
Visits 
Data after 
intercurrent event* 
Primary efficacy 
Change from baseline to Week 4 in SiSBP 
AOBPM 
Main 
Mixed model 
FAS 
Weeks 2,4 
Included 
 
 
Sensitivity 
Multiple imputation (J2R)  
FAS 
Weeks 2,4 
Included 
 
 
 
Multiple imputation (CR)  
FAS 
Weeks 2,4 
Included 
 
 
 
Multiple imputation 
(tipping point)  
FAS 
Weeks 2,4 
Included 
 
 
 
Mixed model 
FAS 
Weeks 2,4 
Excluded 
 
 
Supportive 
Mixed model 
PPS 
Weeks 2,4 
NA 
 
 
 
LOCF-ANCOVA 
FAS 
Weeks 2,4 
Included 
 
 
 
BOCF-ANCOVA 
FAS 
Weeks 2,4 
Included 
 
 
Subgroup 
Mixed model by 
subgroup 
FAS 
Weeks 2,4 
Included 
Key secondary efficacy 
Change from DB-WD baseline (Week 36) to Week 40 
in SiSBP 
AOBPM 
Main 
Mixed model 
mFAS 
Weeks 38,40 
Included 
 
 
Sensitivity 
Multiple imputation (J2R)  
mFAS 
Weeks 38,40 
Included 
 
 
 
Multiple imputation (CR)  
mFAS 
Weeks 38,40 
Included 
 
 
 
Multiple imputation 
(tipping point)  
mFAS 
Weeks 38,40 
Included 
 
 
 
Mixed model 
mFAS 
Weeks 38,40 
Excluded 
 
 
Supportive 
Mixed model 
mPPS 
Weeks 38,40 
NA 
 
 
 
LOCF-ANCOVA 
mFAS 
Weeks 38,40 
Included 
 
 
 
BOCF-ANCOVA 
mFAS 
Weeks 38,40 
Included 
 
 
Subgroup 
Mixed model by 
subgroup 
mFAS 
Weeks 38,40 
Included 


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Endpoint 
Measured 
by 
Analysis 
Model 
Analysis 
set 
Visits 
Data after 
intercurrent event* 
Other secondary efficacy 
Change from baseline to Week 4 in SiDBP 
AOBPM 
 
Mixed model 
FAS 
Weeks 2,4 
Included 
Change from baseline to Week 4 in SiDBP 
AOBPM 
 
Mixed model 
FAS 
Weeks 2,4 
Excluded 
Change from baseline to Week 4 in SiDBP 
AOBPM 
 
Mixed model 
PPS 
Weeks 2,4 
NA 
Change from baseline to Week 4 in 24 h mean SBP  
ABPM 
 
ANCOVA 
aFAS 
Week 4 
Included 
Change from baseline to Week 4 in 24 h mean DBP  
ABPM 
 
ANCOVA 
aFAS 
Week 4 
Included 
Change from DB-WD baseline (Week 36) to Week 40 
in SiDBP 
AOBPM 
 
Mixed model 
mFAS 
Weeks 38,40 
Included 
Change from DB-WD baseline to Week 40 in SiDBP 
AOBPM 
 
Mixed model 
mFAS 
Weeks 38,40 
Excluded 
Change from DB-WD baseline to Week 40 in SiDBP 
AOBPM 
 
Mixed model 
mFAS 
Weeks 38,40 
Included 
Change from DB-WD baseline (Week 36) to Week 40 
in 24 h mean SBP  
ABPM 
 
ANCOVA 
maFAS 
Week 40 
Included 
Change from DB-WD baseline (Week 36) to Week 40 
in 24 h mean DBP  
ABPM 
 
ANCOVA 
maFAS 
Week 40 
Included 
Other efficacy 
Change from baseline to Week 4 in mean daytime SBP 
ABPM 
 
ANCOVA 
aFAS 
Week 4 
Included 
Change from baseline to Week 4 in mean nighttime 
SBP 
ABPM 
 
ANCOVA 
aFAS 
Week 4 
Included 
Change from baseline to Week 4 in mean daytime 
DBP 
ABPM 
 
ANCOVA 
aFAS 
Week 4 
Included 
Change from baseline to Week 4 in mean nighttime 
DBP 
ABPM 
 
ANCOVA 
aFAS 
Week 4 
Included 
Change from DB-WD baseline (Week 36) to Week 38 
in SiSBP 
AOBPM 
 
Mixed model (key 
secondary) 
mFAS 
Weeks 38,40 
Included 
Changes from DB-WD baseline (Week 36) to Weeks 
44 and 48 in SiSBP 
AOBPM 
 
Mixed model 
mFAS 
Weeks 38,40, 
44, 48 
Included 
Changes from DB-WD baseline (Week 36) to Week 38 
in SiDBP 
AOBPM 
 
Mixed model  
mFAS 
Weeks 38,40 
Included 


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Endpoint 
Measured 
by 
Analysis 
Model 
Analysis 
set 
Visits 
Data after 
intercurrent event* 
Changes from DB-WD baseline (Week 36) to Weeks 
44 and 48 in SiDBP 
AOBPM 
 
Mixed model  
mFAS 
Weeks 38,40, 
44, 48 
Included 
Change from DB-WD baseline (Week 36) to Week 40 
in mean daytime SBP 
ABPM 
 
ANCOVA 
maFAS 
Week 40 
Included 
Change from DB-WD baseline (Week 36) to Week 40 
in mean nighttime SBP 
ABPM 
 
ANCOVA 
maFAS 
Week 40 
Included 
Change from DB-WD baseline (Week 36) to Week 40 
in mean daytime DBP 
ABPM 
 
ANCOVA 
maFAS 
Week 40 
Included 
Change from DB-WD baseline (Week 36) to Week 40 
in mean nighttime DBP 
ABPM 
 
ANCOVA 
maFAS 
Week 40 
Included 
Ratio to baseline of UACR 
 
 
Mixed model 
FAS 
Week 2 up to 
Week 36 
Included 
Ratio to DB-WD baseline (Week 36) of UACR 
 
 
Mixed model 
mFAS 
Week 38 up to 
Week 48 
Included 
Time from Randomization to discontinuation of study 
treatment due to lack of efficacy 
 
 
Cox model (two-step) 
FAS 
NA 
NA 
Time from Re‑randomization to discontinuation of 
study treatment due to lack of efficacy 
 
 
Cox model 
mFAS 
NA 
NA 
* In the DB part: Premature DB treatment discontinuation or addition / dose increase of diuretic (whichever comes first); in the DB-WD part: Premature DB-WD treatment discontinuation, 
initiation of antihypertensive rescue medication or addition / dose increase of diuretic (whichever comes first). 
ABPM = ambulatory blood pressure monitoring; aFAS = ABPM Full analysis set; ANCOVA = analysis of covariance; AOBPM = automated office blood pressure measurement; CR = Copy 
Reference; DB = double-blind; DBP = diastolic blood pressure; FAS = Full analysis set; J2R = Jump to Reference; LOCF = last observation carried forward; maFAS = modified ABPM 
Full analysis set; mFAS = modified Full analysis set; mPPS = modified Per‑Protocol set; NA = not applicable; PPS = Per-Protocol Set; SiDBP = (mean trough) sitting diastolic blood 
pressure; SiSBP = (mean trough) sitting systolic blood pressure; UACR = urine albumin-to-creatinine ratio; WD = withdrawal. 
 


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6.7 Analysis of pharmacokinetic variables  
Trough plasma concentrations of aprocitentan are measured at steady state at Week 4. 
Trough is defined as a sample taken in the morning of the Visit 6 prior to study treatment 
administration of Visit 6.  
Aprocitentan plasma concentrations obtained at Week 4 (Visit 6) will be summarized for 
the aprocitentan 12.5 mg and 25 mg groups only. Summary statistics include arithmetic 
mean, SD of the mean, minimum, maximum, median, coefficient of variation (CV%), and 
number of observations. In these calculations, all values below the limit of quantification 
will be set to zero. Additionally, summaries will be created by age category, sex, and race. 
PK data will be listed for all subjects in the aprocitentan 12.5 mg and 25 mg groups as well 
as for those subjects in the placebo group that were included as controls. 
7 
SAFETY VARIABLES AND ANALYSES 
Safety analyses in the DB and SB aprocitentan parts will be performed on the SAF and 
rSAF, respectively. Safety analyses in the DB-WD part will be performed on the mSAF.  
All safety data will be listed. In the unlikely event that a subject receives DB treatment (or 
SB aprocitentan treatment, respectively) without being randomized, this subject will not be 
included in the SAF (or rSAF, respectively), but their safety data will be listed. Similarly, 
in the unlikely event that a subject received DB-WD treatment without being 
re-randomized, this subject will not be included in the mSAF, but their safety data will be 
listed. 
7.1 Adverse events 
7.1.1 Variables 
7.1.1.1 Treatment-emergent adverse events 
The original terms used by the investigators to describe AEs in the Adverse Events eCRF 
are assigned a PT and a SOC for classification and tabulation using MedDRA (last 
available version). 
Subjects who experienced the same AE more than once within a specified time period (as 
qualified by the same PT) are counted only once. 
An event/assessment is treatment-emergent if the onset/assessment date is between the start 
date of the randomized treatment period up to EOT+30 days (begin and end dates included). 
More in particular: 
• An event/assessment is DB treatment emergent if the onset/assessment date is between 
the start date of the DB part up to the day before the start date of the SB treatment part 
(or EOT + 30 days if the subject did not enter the SB part); 


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• An event/assessment is SB treatment emergent if the onset/assessment date is between 
the start date of the SB aprocitentan part up to the day before the start date of the 
DB‑WD treatment part (or EOT + 30 days if the subject did not enter the DB-WD part); 
• An event/assessment is DB-WD treatment emergent if the onset/assessment date is 
between the start date of the DB-WD part up to EOT + 30 days. 
An event/assessment with an onset/assessment date between the start date of the run-in 
period up to the start of randomized treatment period (if the subject is randomized; EOT if 
the subject is not randomized) will be designated as run-in-emergent. 
7.1.1.2 Relationship of treatment-emergent adverse events  
Relationship to study treatment, standardized background antihypertensive therapy and 
study design or protocol-mandated procedures is determined by the investigator as 
‘Unrelated’ or ‘Related’ Adverse Events eCRF. If (even after repeated querying) the 
relationship is missing, the event is considered ‘Related’. 
7.1.1.3 Intensity of treatment-emergent adverse events  
The intensity of an AE is determined by the investigator as ‘mild’, ‘moderate’ or ‘severe’ 
on the Adverse Events eCRF. If an AE increases in severity this will be collected in a 
separate record with a new onset date (including a link to the record with the lower intensity; 
both AEs are considered treatment-emergent and will be analyzed as such). Subjects who 
experienced the same AE more than once within a specified period/part (as qualified by 
the same PT) but with different intensities are counted only once, using the worst reported 
intensity. If (even after repeated querying) the intensity is missing, the event is considered 
severe. 
7.1.1.4 Serious adverse events 
An SAE is defined as an AE where ‘Serious’ is ‘Yes’ the Adverse Events eCRF. 
7.1.1.5 Adverse events leading to discontinuation of study treatment  
These are AEs where ‘Action taken with study treatment (aprocitentan or placebo)’ is 
‘Permanently discontinued’ on the Adverse Events eCRF.  
Notes: AEs starting in the RI period, but leading to discontinuation of study treatment in 
the randomized treatment period will be counted in the latter period; AEs leading to 
discontinuation of standardized background antihypertensive therapy are not counted. 
7.1.1.6 Adverse events of special interest (AESIs)  
AESIs include anaemia (or haemodilution), hepatic disorders, oedema / fluid retention and 
decompensation/aggravation of heart failure. These are defined using MedDRA 
version 24.0 in Appendix 14.3.  


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7.1.2 Analysis 
An overview table will be provided displaying by study part (DB, SB aprocitentan or 
DB-WD) and treatment group (within each study part) the number (%) of subjects with at 
least one treatment-emergent: AE, SAE, AE leading to premature discontinuation of study 
treatment, AESI, MACE and MACE-plus (the latter two as confirmed by adjudication). 
A similar overview table (but without study part and treatment group) will also be provided 
for run-in-emergent AEs based on the RIS. 
Treatment-emergent AEs will be tabulated by study part (DB, SB aprocitentan or DB-WD), 
and treatment group (within each study part), SOC and PTs within each SOC: the number 
and percentage of subjects who experienced at least one AE, at least one AE within each 
SOC and at least one AE within each PT will be displayed. AEs will also be summarized 
by decreasing frequency of PT in the aprocitentan 25 mg group.  
A similar table (but without study part and treatment group) will also be provided for 
run-in-emergent AEs based on the RIS.  
AEs will also be tabulated by maximum intensity and relationship to aprocitentan or 
placebo. Relationship to standardized background antihypertensive therapy will only be 
listed.  
If an AE starts in one study part and ends in the next part without increasing intensity, it is 
counted only in the first part. 
Treatment-emergent SAEs will be summarized in a similar manner as AEs.  
For EudraCT purposes, non-serious and total death / serious AEs will be summarized 
separately by study part. 
AEs leading to premature discontinuation of study treatment will be summarized in a 
similar manner as AEs. AESI (except hepatic disorders) will be summarized by CKD stage 
at Baseline. 
The time from Randomization to (first) oedema / fluid retention AESI in the DB or SB 
aprocitentan part will be summarized by treatment group using Kaplan-Meier plots 
(supplemented by a table displaying the numbers of subjects at risk, those with an event, 
and those censored by treatment group, using weekly intervals). For subjects without 
oedema / fluid retention, the time will be censored at the last dose of DB or SB treatment, 
whichever comes last. Additionally, a ‘two-step’ Cox model with a factor for treatment 
will be fitted [see Section 8.2 for details]. 
The time from Re-randomization to (first) oedema / fluid retention in the DB-WD part will 
be summarized similarly. For subjects without oedema / fluid retention, the time will be 
censored at the last DB-WD treatment + 30 days (or EOS date, whichever comes first) 


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The time from Randomization or Re-randomization to (first) oedema / fluid retention AESI 
in the DB or DB-WD will be summarized by CKD stage at Baseline. 
7.2 Death 
Death information is taken from the Death eCRF. The primary cause of death is reported 
on the same form.  
The number (%) of deaths will be tabulated by study part (DB, SB aprocitentan and 
DB-WD) and treatment group (within study part).  
All deaths will be listed, along with the original terms used by the investigator to describe 
the primary death cause and associated MedDRA PTs. 
7.3 Laboratory tests 
7.3.1 Variables 
Laboratory assessments are performed according to the schedule of assessments [Table 1 
and Table 2]. Laboratory data are evaluated in SI units as provided by the central laboratory. 
The following tests are considered:  
• Hematology: hemoglobin, hematocrit, erythrocyte count, reticulocyte count, leukocyte 
count with differential counts, platelet count, mean corpuscular volume.  
• Clinical Chemistry: aminotransferases (aspartate aminotransferase [AST] / alanine 
aminotransferase [ALT]), alkaline phosphatase, bilirubin and direct bilirubin, 
cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, creatinine, 
eGFR (estimated using the CKD-EPI creatinine equation), urate, albumin, protein, 
glucose, sodium, potassium. 
• Urinalysis: UACR.  
For women of childbearing potential, urine as well as serum pregnancy tests are performed, 
but these results will not be summarized as part of the laboratory data. Positive pregnancy 
tests (if any) will be reported.  
Results of local laboratory tests (collected on the Local Laboratory Hematology and 
Local Laboratory Clinical Chemistry eCRF) will not be used in summaries but will be 
listed. 
Laboratory marked abnormalities are defined in Section 14.2. When determining 
double-blind treatment-emergent marked laboratory abnormalities, all assessments 
(including the unscheduled ones) are considered. 
All assessments (including the unscheduled ones) are considered and re-assigned to the 
most appropriate visit according to the rules described in Section 10.1.2.  


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7.3.2 Analysis 
Changes from baseline for laboratory tests to visits in the DB+SB part will be summarized 
using descriptive statistics by visit and treatment group (in the DB part). Changes from 
DB-WD baseline (Week 36) to visits in the DB-WD part and up to EOS will be summarized 
by visit and treatment group (in the DB-WD part). Data will be displayed in SI units 
whenever possible and graphical approaches will be applied for certain variables.  
Percentage changes from baseline in plasma volume to visits in the DB+SB part will be 
estimated based on baseline (V4) as well as post-baseline (Vx) in hemoglobin and 
hematocrit (as a fraction between 0 and 1) using the following formula [Strauss 1951]: 
𝑒𝑠𝑡𝑖𝑚𝑎𝑡𝑒𝑑 𝑐ℎ𝑎𝑛𝑔𝑒= 100 × ℎ𝑒𝑚𝑜𝑔𝑙𝑜𝑏𝑖𝑛 (𝑉4)
ℎ𝑒𝑚𝑜𝑔𝑙𝑜𝑏𝑖𝑛(𝑉𝑥) × 1 −ℎ𝑒𝑚𝑎𝑡𝑜𝑐𝑟𝑖𝑡 (𝑉𝑥)
1 −ℎ𝑒𝑚𝑎𝑡𝑜𝑐𝑟𝑖𝑡(𝑉4) −100 
Percentage changes from Week 36 (V11) in plasma volume to visits in the DB-WD part 
will be estimated similarly but with V4 replaced by V11. Estimated changes in plasma 
volume will be summarized by visit and treatment group (in the DB+SB part or DB-WD 
part, where appropriate). 
The number (%) of subjects with laboratory marked abnormalities will be tabulated by 
study part (DB, SB, and DB-WD) and treatment group (within study part). In addition, the 
number (%) of subjects with AST or ALT > 3  the ULN combined with 
bilirubin > 2  ULN will be tabulated. In addition, AST or ALT > 5 or 10  ULN will also 
be tabulated. 
7.4 Electrocardiography 
7.4.1 Variables 
A standard 12-lead ECG is performed as defined in the schedule of assessments [Table 1 
and Table 2]. ECG data will be electronically transferred from the ECG laboratory database 
to Idorsia and will not be (re-)calculated.  
The following variables will be evaluated: HR (bpm), PR (ms), QRS (ms), QT (ms), 
QTcB (ms), and QTcF (ms). Note that HR will be evaluated only in the context of the ECG. 
For vital signs, pulse rate will be used based on assessment done during AOBPM. 
ECG abnormalities are defined as follows:  
• QTcF (Fridericia’s formula) maximum value > 450 ms, > 480 ms, or > 500 ms;  
• Maximum increase from baseline in QTcF (Fridericia’s formula) > 30 ms, > 60 ms.  
All assessments (including the unscheduled ones) are considered and re-assigned to the 
most appropriate visit according to the visit windows described in Section 10.1.2. 


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7.4.2 Analysis 
Descriptive statistics by study part (DB+SB and DB-WD), visit and treatment group 
(within study part) will be provided for observed values and absolute changes from baseline 
(or DB-WD baseline (Week 36), where appropriate) in numeric 12-lead ECG values (HR, 
PR, QRS, QT, QTcB, QTcF).  
The number (%) of subjects with treatment-emergent ECG abnormalities will be 
summarized by study part (DB, SB, and DB-WD), visit and treatment group (within study 
part). These are presented cumulatively, e.g., a QTc value of 501 ms is reported in 
the > 450 ms (H), > 480 ms (HH) and > 500 ms (HHH) categories; the same applies to 
abnormalities related to changes from baseline (or Week 36, where appropriate). 
ECG findings will be summarized by study part (DB, SB, and DB-WD) and treatment 
group (within study part). 
7.5 Vital signs and body weight 
7.5.1 Variables 
Body weight and pulse rate (this term is used to distinguish it from heart rate measured by 
ECG) are assessed according to the schedule of assessments [Table 1 and Table 2]. Pulse 
rate is measured simultaneously with AOBPM and the average of four readings (calculated 
by the vendor) will be used in the analysis. All assessments (including the unscheduled 
ones) are considered and re-assigned to the most appropriate visit according to the visit 
windows described in Section 10.1.2. 
7.5.2 Analysis 
Descriptive statistics by study part (DB+SB and DB-WD), visit and treatment group 
(within study part) will be provided for observed values as well as absolute changes from 
baseline to each visit in the DB and SB parts and from DB-WD baseline (Week 36) to each 
visit in the DB-WD part and up to EOS for body weight and pulse rate.  
7.6 Other safety variables and analyses 
7.6.1 Treatment-emergent MACE and MACE-plus 
MACE is defined as cardiovascular death, non-fatal myocardial infarction, or non‑fatal 
stroke. MACE-plus includes, in addition, hospitalization for heart failure. The analyses will 
focus on MACE-plus. 
Treatment-emergent MACE-plus events confirmed by the CAC are reported on the 
Consensus Event Adjudication Form. The number (%) of subjects with confirmed 
MACE-plus and sub-categories (i.e., death, non-fatal myocardial infarction, non‑fatal 
stroke, or hospitalization for heart failure) will be tabulated by study part (DB, SB 
aprocitentan, or DB-WD) and treatment group (within study part). MACE-plus will be 
summarized by CKD stage at Baseline. 


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If there are at least 12 subjects with an adjudication confirmed MACE-plus, the time from 
Randomization to (first) MACE-plus in the DB or SB aprocitentan part will be summarized 
by treatment group using Kaplan-Meier plots (supplemented by a table displaying the 
numbers of subjects at risk, with an event and censored by treatment group, using weekly 
intervals). For subjects without MACE-plus, the time will be censored at the last dose of 
DB or SB treatment (whichever comes last). Additionally, a ‘two-step’ Cox model with a 
factor for treatment will be fitted [see Section 8.2 for details]. 
If there are at least 12 subjects with an adjudication confirmed MACE -plus, the time from 
Re-randomization to (first) MACE-plus in the DB-WD part will be summarized similarly, 
except that the Cox model is the conventional one. For subjects without MACE-plus, the 
time will be censored at the last dose of DB-WD treatment + 30 days (or EOS date, 
whichever comes first). 
For each treatment group, exposure-adjusted MACE-plus incidence rates will be provided 
per 100 subject-years. The exposure-adjusted incidence rate is calculated as the total 
number of subjects who experienced the MACE-plus event, divided by the total 
subject‑time at risk during each study part. For subjects who had the MACE-plus event 
while on study treatment, subject-time at risk is the time from start date of study treatment 
to date of first event in the respective study part. For subjects who did not experience the 
MACE-plus event, subject‑time at risk is the duration of study treatment in the respective 
study part. The total subject-time at risk is the sum of all the subject-times at risk. These 
tables will include the total number of subjects, the total subject-years on study, the total 
subject-years at risk per event, and the incidence rate (number of subjects with the event / 
total subject-years at risk for the event × 100). An exact 95% CI will be constructed based 
on the Poisson distribution. 
7.6.2 Increase in dose of existing diuretic or addition of new diuretic due to fluid 
retention 
A ‘diuretic due to fluid retention’ is any medication on the Previous/Concomitant 
Medications eCRF as defined in Appendix 14.4 with the indication ‘Adverse Event’ where 
the ‘Main Event’ is fluid retention as defined in Appendix 14.3. The existing diuretic is 
25 mg hydrochlorothiazide as part of the standardized background antihypertensive 
therapy. 
This endpoint will be analyzed similarly to MACE-plus. 
7.6.3 Analysis of biomarker variables 
Ratios to baseline of NT-proBNP will be log transformed (base e). Observed values at 
Baseline, visits in DB and SB part, and changes from baseline (including the geometric 
mean [and SD] ratio of post-baseline to baseline) will be summarized using descriptive 
statistics. Ratios to DB-WD baseline of NT-proBNP in the DB-WD part and up to EOS 
will be analyzed similarly, but with baseline replaced by DB-WD baseline. 


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Ratios to baseline of Mid-regional pro-atrial natriuretic peptide and Troponin will be 
analyzed similarly to NT-proBNP. 
The analysis of biomarkers characterizing the endothelin system and renin angiotensin 
system activity will be addressed in a separate SAP. 
7.7 Overview of safety analyses  
The safety analyses are summarized here: 
Table 5 
Summary of safety analyses 
Endpoint 
Part 
Analysis 
set 
Visits 
Statistical analysis 
(if applicable) 
Adverse events 
DB 
SAF 
NA 
 
SB 
rSAF 
NA 
 
DB-WD 
mSAF 
NA 
 
Serious adverse events 
DB 
SAF 
NA 
 
SB 
rSAF 
NA 
 
DB-WD 
mSAF 
NA 
 
Adverse events leading to 
treatment discontinuation 
DB 
SAF 
NA 
 
SB 
rSAF 
NA 
 
DB-WD 
mSAF 
NA 
 
Adverse event of special interest 
DB 
SAF 
NA 
 
SB 
rSAF 
NA 
 
DB-WD 
mSAF 
NA 
 
 
Laboratory values and changes 
from baseline 
DB+SB 
SAF 
Week 4, 6, 12, 
20, 28 and 36 
 
Laboratory values and changes 
from DB-WD baseline (Week 36) 
DB-WD 
mSAF 
Week 40, 44 
and 48 
 
Number (%) of subjects with 
marked abnormalities laboratory 
values  
DB, 
SAF 
NA 
 
SB 
rSAF 
 
 
DB-WD 
mSAF 
NA 
 
 
Vital signs values and changes 
from baseline over time 
DB+SB 
SAF 
Week 2 up to 
Week 36 
 
Vital signs values and changes 
from DB-WD baseline (Week 36) 
over time 
DB-WD 
mSAF 
Week 38 up to 
Week 48 
 
ECG values over time and 
changes from baseline over time 
DB+SB 
SAF 
Week 2 up to 
Week 36 
 


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Endpoint 
Part 
Analysis 
set 
Visits 
Statistical analysis 
(if applicable) 
ECG values over time and 
changes from DB-WD baseline 
(Week 36) over time 
DB-WD 
mSAF 
Week 48 
 
Number (%) of subjects with 
marked abnormalities ECG values 
DB 
SAF 
NA 
 
SB 
rSAF 
 
 
DB-WD 
mSAF 
NA 
 
 
MACE-plus 
DB+SB 
SAF 
NA 
Cox model 
DB-WD 
mSAF 
NA 
Cox model 
MACE-plus 
All 
SAF 
NA 
Incidence rate  
Increase or addition of diuretic 
DB+SB 
SAF 
NA 
Cox model 
DB-WD 
mSAF 
NA 
Cox model 
DB = double-blind; DB-WD = double-blind withdrawal; ECG = electrocardiogram; MACE = major adverse cardiac 
event; mSAF = modified Safety analysis set; NA = Not applicable as not by visit; NT-proBNP = N-Terminal 
pro‑brain natriuretic peptide; rSAF = restricted Safety analysis set; SAF = Safety analysis set; SB = single‑blind. 
8 
GENERAL STATISTICAL METHODOLOGY 
8.1 General rules for data presentations 
When data are summarized by study part and treatment group one of the following 
presentations will be used. 
For the DB part: 
Aprocitentan 12.5 mg 
N = xxx 
Aprocitentan 25 mg 
N = xxx 
Placebo 
N = xxx 
 
For the SB aprocitentan part: 
Aprocitentan 
25 mg  
N = xxx 
 


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For the combined DB+SB part: 
 
Aprocitentan 
12.5 mg 
N = xxx 
Aprocitentan 
25 mg 
N = xxx 
Placebo 
N = xxx 
DB part  
xx 
xx 
xx 
SB part  
By randomized treatment group  
xx 
xx 
xx 
SB part  
Combined treatment group 
 
xx 
 
 
For the DB-WD part: 
Aprocitentan 25 mg 
N = xxx   
Placebo  
N = xxx 
 
Here N indicates the number of subjects in a treatment group in the analysis set. 
Listings for other than safety variables will be sorted by randomized treatment 
(A = aprocitentan 12.5 mg, B = aprocitentan 25 mg, C = placebo), re-randomized 
treatment (D = aprocitentan 25 mg, E = placebo), country, subject number (ascending) and, 
when appropriate, by visit / date of assessment (ascending). Subjects who are not 
re-randomized will be listed after those who are re-randomized. Run-in failures (i.e., 
subjects in run-in who were not randomized) will be listed next and labeled ‘RI failure’ 
and screening failures (i.e., screened subjects who did not enter the run-in) will be listed 
last and labeled ‘SCR failure’. 
In listings for safety variables, randomized and re-randomized treatment will be replaced 
by actual treatment in the DB and DB-WD parts, respectively. 
Unless noted otherwise, the following descriptive statistics will be used:  
• Number (%) of subjects for categorical variables (missing will not be included in the 
calculation of %). 
• Number of non-missing values, mean, SD, median, Q1, Q3, minimum, maximum for 
continuous variables. 
• The category missing will be displayed only if there are missing values. 


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8.2 Analysis details 
8.2.1 Mixed model for repeated measurements 
This model is used, for example, for the main analyses of the primary and the key secondary 
endpoints.  
Assuming the data are in ‘long’ format (i.e., one row for each subject/visit) example SAS® 
statements for the primary endpoint analysis are: 
proc mixed data=db; 
  class subjid trt01pn avisitn; 
  model chg=trt01pn avisitn trt01pn*avisitn base base*avisitn/ ddfm=kr; 
  repeated avisitn/ subject=subjid type=un; 
  lsmeans trt01pn*avisitn/ diff=control (‘3’ ‘6’) alpha=0.025; 
run;  
The data set db includes baseline SiSBP (base) as well as changes (chg) from baseline to 
Weeks 2 and 4. Furthermore, trt01pn equals 1, 2 and 3 for aprocitentan 12.5 mg, 
aprocitentan 25 mg and placebo in the DB part, respectively, and avisitn is 5 and 6 for 
Weeks 2 and 4, respectively. The Bonferroni correction [Section 6.1] will be applied by 
comparing the two-sided p‑values vs 0.025 (rather than adding adjust=bonf to the lsmeans 
statement). 
Again, assuming the data are in ‘long’ format example SAS® statements for the secondary 
endpoint analysis are: 
proc mixed data=dbwd; 
  class trt01pn subjid trt03pn avisitn; 
  model chg=trt01pn trt03pn avisitn trt03pn*avisitn wk36 wk36*avisitn/ 
ddfm=kr; 
  repeated avisitn/ subject=subjid type=un; 
  lsmeans trt03pn*avisitn/ diff=control (‘5’ ‘13’) alpha =0.05(1); 
run; 
The data set dbwd includes DB-WD baseline (Week 36) SiSBP (wk36) as well as changes 
(chg) from DB-WD baseline (Week 36)  to Weeks 38 and 40. Furthermore, trt03pn equals 
4 and 5 for aprocitentan 25 mg and placebo in the DB-WD part, respectively, and avisitn 
is 12 and 13 for Weeks 38 and 40, respectively. Note that trt01pn (treatment in the DB part) 
is now used as a stratum.  
(1) The alpha level needs to be adjusted to 0.025 in case one of H10 and H20 has been rejected. 


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8.2.2 Controlled imputation assuming missing not at random 
Sensitivity analyses assuming the data are MNAR in the aprocitentan groups (and MAR in 
the placebo group) will be performed using MI. These will be performed assuming a 
monotone missing data pattern (i.e., if data are missing at a given visit, they are also missing 
at subsequent visits). Any non-monotone missing data will first be imputed under MAR, 
which is considered reasonable because the proportion of non‑monotone missing data (i.e., 
AOBPM missing at Week 2, but observed at Week 4) is expected to be low.  
Assuming the data are in ‘wide’ format (i.e., one row for each subject and a variable for 
each visit) example SAS® statements for the primary endpoint are: 
proc mi data=db nimpute=250 seed=63496 out=mono; 
  var base chg2 chg4;  
  mcmc impute=monotone; 
run; 
Here chg2 and chg4 are the changes from baseline to Weeks 2 and 4 in SiSBP, respectively. 
Note that treatment is not included in the imputation model. 
Two control-based MI analyses will be performed under MNAR, a CR and a J2R approach 
[Carpenter 2013]. In these approaches, MI of missing values will be performed based on 
the assumption that subjects with missing data in the aprocitentan arms follow the 
trajectory of the placebo arm, conditional on subjects’ data available prior to 
discontinuation (baseline as well as available post-baseline SiSBP for the CR approach; 
baseline SiSBP only for the J2R approach). Imputation is performed sequentially, one visit 
at a time [Ratitch 2013]. At each visit a regression model is fitted using data from the 
placebo arm only, so missing data in the aprocitentan arms are imputed based on the 
predicted outcome in the placebo arm.  
The SAS® statements for the CR approach are: 
proc mi data=mono nimpute=1 seed=133055 out=CR1; 
  by _Imputation_; 
  class trt01pn; 
  var base chg2; 
  monotone regression; 
  mnar model (chg2/ modelobs=(trt01pn=‘3’)); 
run; 
 
proc mi data=CR1 nimpute=1 seed=130871 out=CR2; 
  by _Imputation_; 
  class trt01pn; 
  var base chg2 chg4; 


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  monotone regression; 
  mnar model (chg4/ modelobs=(trt01pn=‘3’)); 
run; 
The variable _Imputation_ is created by the PROC MI statement that generated the 
monotone missing data. Note that the second PROC MI statement for the CR approach 
includes change from baseline to Week 2 as a predictor for change from baseline to Week 4, 
meaning that subjects from the aprocitentan groups who discontinue DB treatment between 
Week 2 and Week 4 are regarded as subjects from the placebo group with a similar change 
from baseline to Week 2 in SiSBP.  
The SAS® statements for the J2R approach are: 
proc mi data=mono nimpute=1 seed=130340 out=J2R1; 
  by _Imputation_; 
  class trt01pn; 
  var base chg2; 
  monotone regression; 
  mnar model (chg2/ modelobs=(trt01pn=‘3’)); 
run; 
 
proc mi data=J2R1 nimpute=1 seed=125892 out=J2R2; 
  by _Imputation_; 
  class trt01pn; 
  var base chg4; 
  monotone regression; 
  mnar model (chg4/ modelobs=(trt01pn=‘3’)); 
run; 
Note that the second PROC MI statement for the J2R approach does not include change 
from baseline to Week 2 as a predictor for change from baseline to Week 4, meaning that 
subjects from the aprocitentan groups who discontinue DB treatment between Week 2 and 
Week 4 are ‘immediately’ regarded as subjects from the placebo group.  
The resulting multiple data sets are subsequently analyzed using the same mixed model as 
for the main analysis. For this purpose, the data set from PROC MI (CR2 or J2R2 in the 
example), should be transposed to a ‘long’ format.  
Results from these analyses are combined using Rubin’s methodology [Rubin 1987] 
implemented in SAS® PROC MIANALYZE: 
proc mianalyze parms=diffs; 
  class trt01pn avisitn; 
  modeleffects trt01pn* avisitn; 


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run; 
The control-based MI models described above are pattern-mixture models, where the 
patterns are defined based on the subject’s last visit. If the number of subjects with missing 
Week 4 data is greater than expected (i.e., > 5% of the FAS), the reason for premature 
discontinuation (lack of efficacy, AE, other) may also be considered in defining the patterns. 
The SAS® statements for the key secondary endpoint are similar, only with DB-WD 
baseline (Week 36), Week 38 and Week 40 instead of baseline, Week 2 and Week 4, 
respectively. 
8.2.3 Tipping point analysis assuming missing not at random  
The tipping point analysis will be performed using MI assuming a monotone missing data 
pattern. Any non-monotone missing data will first be imputed under MAR, as described in 
Section 8.2.2. Missing data will initially be imputed under MAR, but the aprocitentan 
groups will be ‘penalized’ by adding a shift of s mmHg to each imputed value. This will 
be done for a series of s values (henceforth, shift parameters). Only positive shift 
parameters will be considered since these correspond to a smaller reduction or larger 
increase in BP. For each shift parameter the multiple data sets are analyzed using an 
ANCOVA for the last time point (for the primary endpoint this is chg4, the change from 
baseline to Week 4 in SiSBP) and the results are combined using PROC MIANALYZE. 
This is implemented in the following SAS® macro: 
%macro tippoint (dset=, smin=, smax=, step=, seed=, out=); 
* data set &dset should be in wide format; 
 
* obtain monotone missing data pattern; 
proc mi data=&dset nimpute=250 seed=&seed out=mono;  
  var base chg2 chg4; 
  mcmc impute=monotone; 
run; 
 
proc sort; 
  by _Imputation_; 
run; 
 
data &out; 
  set _null_; 
run; 
 
ods select none; 
%do s=smin %to &smax %by &step; 
proc mi data=mono nimpute=1 seed=&seed out=tip; 


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  by _Imputation_; 
  class trt01pn; 
  var trt01pn base chg2 chg4; 
  monotone regression; 
  mnar adjust(chg4/ shift=&s adjustobs=(trt01pn=‘1’)); 
  mnar adjust(chg4/ shift=&s adjustobs=(trt01pn=‘2’)); 
run; 
 
ods output diffs=diffs; 
proc mixed data=tip; 
  by _Imputation_; 
  class trt01pn; 
  model chg4=trt01pn base; 
  lsmeans trt01pn/ diff=control(‘3’); 
run; 
ods output close; 
 
ods output parameterestimates=parmest; 
proc mianalyze parms=diffs; 
  class trt01pn; 
  modeleffects trt01pn; 
run; 
ods output close; 
 
data parmest; 
  shift=&s; 
  set parmest; 
run; 
 
data &out; 
  set &out parmest; 
run; 
%end; 
ods select all; 
%mend tippoint; 
An example of the associated macro call is: 
%tippoint (dset=mono, smin=0, smax=50, step=1, seed=125160, out=tipout); 
The p-value in data set tipout can be plotted vs the shift parameter. The shift parameter at 
which statistical significance is lost (in the DB part when the two-sided P > 0.025) indicates 


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how severe departures from the MAR assumption must be to overturn the conclusions of 
the main analysis.  
The tipping point analyses for the DB-WD part are similar to those for the DB part, except 
that baseline, Week 2 and Week 4 are replaced by DB-WD baseline (Week 36), Week 38 
and Week 40, respectively, and the shift applies to the aprocitentan 25 mg group only. 
8.2.4 Two-step Cox model 
The two-step Cox model [Anderson 1982] is an extension of the conventional Cox model 
allowing for different treatment effects in different time intervals. The conventional Cox 
model comparing two treatments vs placebo can be fitted using the SAS® statements like: 
proc phreg data=<data>; 
  model t*e(0)=treat1 treat2/ risklimits ties=breslow; 
run; 
Here treat1 and treat2 are treatment indicators (treat1 = 1 for treatment 1, 0 otherwise; 
treat2 = 1 for treatment 2, 0 otherwise; placebo will have treat1 = treat2 = 0), t is the time 
to event and e is an event indicator (1 = event; 0 = no event). The treatment effects are 
exponentiated to become hazard ratios vs placebo and by using risklimits their 95% CIs are 
obtained. 
In the two-step Cox model the time axis is divided in two time intervals 0 < t ≤ C and t > C 
where the value of C is pre-specified. It can be fitted using SAS® statements like: 
proc phreg data=<data>; 
  model t*e(0)=treat11 treat12 treat21 treat22/ risklimits 
ties=breslow; 
  treat11=treat1*(t<=C); 
  treat12=treat1*(t>C); 
  treat21=treat2*(t<=C); 
  treat22=treat2*(T>C); 
run; 
Here treat11 and treat12 are time-dependent covariates indicating the effect of treatment 
1 in the first (t ≤ C) and second (t > C) interval, respectively. Similarly, treat21 and treat22 
indicate the effect of treatment 2 in the first and second interval, respectively.  
In this study the two intervals are the SB and the DB aprocitentan part, respectively, so 
C = 28 days. (C may be fine-tuned on a subject level using the DB treatment end day [see 
Section 10.1.1]). The two-step Cox model gives hazard ratios for aprocitentan 12.5 mg vs 
placebo and aprocitentan 25 mg vs placebo for the DB part as well as the SB aprocitentan 
part in a single analysis. Note that in the latter part all subjects receive aprocitentan 25 mg, 
so an analysis based on treatment in the preceding DB part is somewhat artificial. However, 


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the two-step Cox model ensures that all events are included in the analysis and enables the 
assessment of ‘prolonged’ treatment effects (if any). 
8.2.5 Control/response analysis 
This analysis will be implemented by the following SAS® statement: 
proc freq; 
tables treatment*response / nocol nopercent cmh1 commonriskdiff; 
run; 
 
For DB-WD the analysis should be stratified by DB treatment, so treatment in DB (trt01pn) 
needs to be added in the tables statement. 
9 
INTERIM ANALYSES  
No interim analysis will be performed. 
10 GENERAL DEFINITIONS AND DERIVATIONS 
Baseline is defined as the last available measurement before or on the day of randomization. 
The date and time of randomization are taken from the IXRS Subject eCRF. 
DB-WD baseline (Week 36) is defined as the last available measurement before or on the 
day of Re-randomization. The date and time of re-randomization are taken from the IXRS 
Subject eCRF. 
If both date and time of the measurement are collected, baseline is the last measurement up 
to the date and time of randomization. If only the date is collected, baseline is the last 
measurement before the date of randomization. 
10.1 Analysis periods and visit windows 
10.1.1 Analysis periods 
The screening period is defined as the time from the informed consent date until one day 
before the run-in period start date (or EOS if the subject does not enter the run-in). 
The RI period begins at the date of the first dose of RI treatment and ends at the date of 
the last dose of RI treatment, collected on the Study Treatment Log where ‘Study Period’ 
is ‘Single Blind Run-in’.  
The randomized treatment period begins at the DB treatment start date and ends at the 
last of the treatment stop dates collected on the Study Treatment Log where ‘Study Period’ 
is not ‘Single Blind Run-in’ and the reason for treatment end is not ‘Interruption due to an 
AE’ or ‘Interruption not due to an AE’. 


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The randomized treatment period is divided into three parts: DB, SB aprocitentan and 
DB‑WD.  
• The DB part begins at the DB treatment start date and ends at the DB treatment stop 
date collected on the Study Treatment Log where ‘Study Period’ is ‘Double-Blind 
Treatment (Part 1)’ and the reason for treatment end is not ‘Interruption due to an AE’ 
or ‘Interruption not due to an AE’. 
• The SB aprocitentan part begins at the SB treatment start date and ends at the SB 
treatment stop date collected on the Study Treatment Log where ‘Study Period’ is 
‘Single-Blind Treatment (Part 2)’ and the reason for treatment end is not ‘Interruption 
due to an AE’ or ‘Interruption not due to an AE’. 
• The DB-WD part begins at the DB-WD treatment start date and ends at the DB-WD 
treatment stop date collected on the Study Treatment Log where ‘Study Period’ is 
‘Double-Blind Withdrawal Treatment (Part 3)’ and the reason for treatment end is not 
‘Interruption due to an AE’ or ‘Interruption not due to an AE’. 
Should there be any ‘gap’ between the end of one period and the start of the next, then the 
gap days are allocated to the former period. In the unlikely case that the gap is more than 
30 days, gap days 31, 32, etc. will not be allocated to a study part.  
The safety FU period begins one day after the end of the randomized treatment period and 
ends at the date of the EOS visit. Safety data obtained during the safety FU period or at the 
EOS visit will be allocated to the last part of the subject’s randomized treatment period. 
This is restricted to data collected up to EOT+30 days. Safety data collected beyond that 
time point will not be allocated to a study part. 
10.1.2 Visit windows  
For visit-based variables (for visits see schedule of assessments in Table 1 and Table 2), 
analysis windows are based on study day numbers defined as follows: 
Study day is defined for the entire study as assessment date minus randomization date 
plus 1 day. Thus, the day of randomization is study Day 1. For dates prior to randomization, 
study day is the negative number of days between the date under consideration and the date 
of randomization. Thus, the day before randomization date is study Day −1. Study Day 0 
does not exist. 
Withdrawal (WD) day is defined for the DB-WD part as assessment date minus 
re‑randomization date plus 1 day. If a subject is not re-randomized, then WD day is not 
defined. 
The analysis windows around the visits are given in Table 6. For efficacy variables (except 
for ABPM measurements) and safety analyses the windows are based on study or WD days 
and on the start and stop dates of the study parts defined above.  


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Table 6 
Visit windows 
 
Target 
Efficacy 
Safety 
Visit 
Study day 
WD day 
Lowera 
Uppera 
Lowera 
Uppera 
DB part 
 
 
 
 
 
 
4 (Randomization) 
1 
- 
 
1 
 
1 
5 (Week 2) 
14 
- 
8 
20 
2 
20 
6 (Week 4) 
28 
- 
21 
36b 
21 
36b 
SB aprocitentan part 
 
 
 
 
 
 
7 (Week 6) 
42 
- 
37c 
62 
37c 
62 
8 (Week 12) 
84 
- 
63 
111 
63 
111 
9 (Week 20) 
140 
- 
112 
167 
112 
167 
10 (Week 28) 
198 
- 
168 
223 
168 
223 
11.1 (Week 36) 
252 
- 
224 
258d 
224 
258d 
DB-WD part 
 
 
 
 
 
 
11.2 (Re-randomization) 
- 
1 
 
1 
 
1 
12 (Week 38) 
266 
14 
8 
20 
2 
20 
13 (Week 40) 
280 
28 
21 
41 
21 
41 
14 (Week 44) 
308 
56 
42 
69 
42 
69 
15 (Week 48) 
336 
84 
70 
97 
70 
97e 
EOS (EOT + 30 days) 
366 
114 
NA 
NA 
98 
 
a vs study day for the DB part and vs WD day for DB-WD part. b Or end of DB treatment part + one day (whichever 
comes first). c But not before start of SB aprocitentan part (whichever comes first). d Or end of SB aprocitentan 
part + one day (whichever comes first). e Or end of DB-WD treatment part + one day (whichever comes first). 
DB = double-blind; NA=Not applicable; WD = withdrawal. 
 
If there is more than one value within the same visit window, the value closest to the 
planned assessment date will be taken. Where multiple assessments fall on the same day 
or have the same visit label, then the latest in time is used (or with the highest SDTM 
sequence number, if time is not collected). In the event of equidistant values from the 
planned time point, the last assessment will be considered for the analyses. If there are 
records ‘on-treatment’ and ‘off treatment’ within the same visit window, use only those 
‘on‑treatment’. 
If measurements involve time, the following target times should be considered: 
• Target day/time = Target day and time 12:00 
• Lower day/time = Lower day and time 0:00 
• Upper day/time = Upper day and time 23:59 


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AOBPM measurements (efficacy) will also have indicator whether the measurement was 
‘on-treatment’. A measurement is considered on-treatment if it was taken before or within 
one day2 of the end of the randomized treatment period (defined above). 
10.2 Handling of incomplete dates 
In the following, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, 
respectively, of a possible date. The ‘lower limit’ and ‘upper limit’ refer to the earliest and 
latest possible dates, respectively. As an example: if start date is ‘MAR2017’ (i.e., day 
missing), the lower limit is 01MAR2017 and the upper limit is 31MAR2017; if start date 
is ‘2017’ (i.e., day and month missing), the lower limit is 01JAN2017 and the upper limit 
is 31DEC2017. For time from first diagnosis of hypertension, take the lower limit. 
10.2.1 Adverse events 
The purpose of imputing AE dates is only to assign an AE to a specific treatment phase for 
the summary tables. No imputed date is considered in the medical evaluation of an AE. 
The imputation for incomplete AE dates in given in Table 7. 
Table 7 
Imputation rules for an incomplete or missing AE date 
Field 
Incomplete date 
Missing date 
AE resolution 
date 
The upper limit. 
No 
imputation; 
the 
AE 
is 
considered as ongoing. 
AE onset date 
The below rule applies. 
1.If the (imputed) resolution date is on or after 
the start of the <study treatment> and if the start 
of the <study treatment> falls within the upper 
and lower limits (inclusive), the <study 
treatment> start date is used 
2. If the resolution date is missing and the 
<study treatment> start date falls within the 
upper and lower limits (inclusive) the <study 
treatment> start date is used 
In all other cases the lower limit is used. 
Whichever is the earlier of the 
date of resolution and the <study 
treatment> start date. 
Depending on the analysis, <study treatment> is SB placebo, DB, SB aprocitentan or DB-WD treatment. 
                                                 
2 If the randomized treatment period ends at study Day x then an AOBPM measurement taken at Day x + 1 will be ‘on 
treatment’, but a measurement taken at Day x + 2 will be ‘off-treatment’. 


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After applying the rules above, it may be that an AE can be allocated to multiple study 
parts. In that case, it will be allocated one study part according to the following priority: 
(1) DB part, (2) DB-WD part, (3) SB aprocitentan part and (4) RI period. 
10.2.2 Concomitant therapies 
The purpose of imputing concomitant therapy / antihypertensive therapy dates is only to 
assign a concomitant therapy to a specific treatment phase for the summary tables. No 
imputed date is considered in the medical evaluation of a concomitant therapy / 
antihypertensive therapy.  
Table 8 
Imputation rules for an incomplete or missing concomitant therapy 
or antihypertensive therapy date 
Field 
Incomplete date 
Missing date 
Concomitant therapy / 
Antihypertensive therapy 
end date 
The upper limit. 
No imputation; the therapy 
is considered as ongoing. 
Concomitant therapy / 
Antihypertensive therapy 
start date 
The rules below apply in the order presented: 
1. If the (imputed) end date is on or after the 
start of the <study treatment> and if the start of 
the <study treatment> falls within the upper and 
lower limits (inclusive), the <study treatment> 
start date is used. 
2. If the end date is missing and the <study 
treatment> start date falls within the upper and 
lower limits (inclusive) the <study treatment> 
start date is used. 
3. In all other cases the lower limit is used. 
If the concomitant therapy is flagged as PRIOR 
TO FIRST DOSE and the start date is 
completely missing; the <study treatment> start 
date – 1 day is used. 
Whichever is the earlier of 
the concomitant therapy / 
Antihypertensive therapy 
end 
date 
or 
<study 
treatment> start date. 
Depending on the analysis, <study treatment> is SB placebo, DB, SB aprocitentan or DB-WD treatment. 
 
After applying the rules above, it may be that a concomitant medication can be allocated 
to multiple study parts. In that case, it will be allocated one study part according to the 
following priority: (1) DB part, (2) DB-WD part, (3) SB aprocitentan part and (4) RI period. 


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11 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL 
In other efficacy endpoints [section 6.1.3 of the protocol]: 
• Discontinuation of randomized study treatment due to confirmed grade 3 (i.e., mean 
SiSBP/SiDBP ≥ 180/110 mmHg, respectively) hypertension [see section 6.1.3 of the 
protocol, version 2, D-18.214]  
is replaced by [Section 6.5.1 of this SAP]: Discontinuation of study treatment due to lack 
of efficacy. 
Also, in other efficacy endpoints [section 6.1.3 of the protocol]: 
• Ratios to baseline for all assessed time points of DB, SB and DB-WD parts in UACR 
is replaced by [Section 6.5.1 of this SAP]: 
• Ratios to baseline for all assessed time points in the DB and SB aprocitentan parts and 
ratios to DB-WD baseline (Week 36) for all assessed time points in the DB-WD part 
in UACR. 
In the supportive analyses for the primary endpoint [section 10.3.2.4 of the protocol] LOCF 
and BOCF analyses were added [Section 6.2.5 of this SAP]. In the supportive analyses for 
the key secondary endpoint [section 10.3.3.4 of the protocol] a BOCF analysis was added 
[Section 6.3.5 of this SAP]. 
In the SAP Version 1 and protocol, the baseline for the DB-WD part was referred to as 
‘Week 36’. It has now been renamed to ‘DB-WD baseline (Week 36)’ and defined as the 
last assessment before or on the day of re-randomization which may be before Week 36. 
Analysis of AESIs was added to the SAP.  
Specifications and analyses related to the COVID-19 pandemic were added to the SAP 
[D‑20.063]. 
The estimand strategy was changed from that laid out in the protocol [version 3, D-20.008], 
following comments from regulatory agencies. In brief, the treatment policy strategy is 
now used for the main estimands, whereas the hypothetical strategy is now used for 
supplementary estimands. 
In detail: in the description of statistical analyses [section 10.3 of the protocol, version 3, 
D-20.008], for the main analyses in the DB and DB-WD parts, it was specified that: 
• AOBPM measurements obtained after premature discontinuation of DB or DB-WD 
treatment will be excluded from this analysis (i.e., considered as missing), leading to a 
hypothetical strategy estimand in the terminology of [ICH E9 (R1)]. 


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This was replaced by [see Section 6.2.2 and 6.3.2 of this SAP]: 
• All AOBPM measurements obtained after premature discontinuation of DB or DB-WD 
treatment or the addition/dose increase of a diuretic will be included in the main 
analysis, leading to a treatment policy strategy estimand in ICH terminology 
[ICH 2017b]. 
A hypothetical strategy estimand will be used in sensitivity analyses [see Sections 6.5.1 
and 6.3.4 of this SAP]. 
Endpoints related to BP control and response were added as exploratory endpoint [see 
Sections 6.5.1 and 6.5.2 of this SAP]. 
12 LIST OF TABLES, LISTINGS AND FIGURES 
The list of Tables, Listings and Figures is available in Idorsia’s Electronic Document 
Management System. 
13 REFERENCES 
[D-18.214] Multi-center, blinded, randomized, PaRallEl-group, Phase 3 study with 
aproCItentan in Subjects with ResIstant HypertensiON (RHT). Idorsia 
Pharmaceuticals 
Ltd; 
Protocol 
ID-080A301 
(PRECISION) 
Version 
2, 
19 September 2018. 
[D-20.008] Multi-center, blinded, randomized, PaRallEl-group, Phase 3 study with 
aproCItentan in Subjects with ResIstant HypertensiON (RHT). Idorsia 
Pharmaceuticals 
Ltd; 
Protocol 
ID-080A301 
(PRECISION) 
Version 
3, 
27 February 2020. 
[D‑20.063] Multi-center, blinded, randomized, PaRallEl-group, Phase 3 study with 
aproCItentan in Subjects with ResIstant HypertensiON (RHT). Idorsia 
Pharmaceuticals Ltd; Protocol addendum ID-080A301 (PRECISION), 8 April 2020. 
[Anderson 1982] Anderson JA, Senthilselvan A. A Two-Step Regression Model for 
Hazard Functions. J R Stat Soc Ser C Appl Stat 1982;31:44–51. 
[Bretz 2009] Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to 
sequentially rejective multiple test procedures. Stat Med 2009;28:586–604. 
[Carpenter 2013] Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials 
with protocol deviation: A framework for relevant, accessible assumptions, and 
inference via multiple imputation. J Biopharm Stat 2013;23:1352–71. 


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[ICH 2017a] ICH E17: General principles for planning and design of multi-regional 
clinical trials. 16 November 2017. Accessed on 14 November 2018. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficac
y/E17/E17EWG_Step4_2017_1116.pdf. 
[ICH 2017b] ICH E9 (R1): Addendum on estimands and sensitivity analysis in clinical 
trials to the guideline on statistical principles for clinical trials. 16 June 2017. 
Accessed on 7 May 2018. Available from: 
 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E9/E9-R1EWG_Step2_Guideline_2017_0616.pdf. 
[Levey 2009] Levey AS, Cattran D, Friedman A, Miller WG, Sedor J, Tuttle K, et al. 
Proteinuria as a Surrogate Outcome in CKD: Report of a Scientific Workshop 
Sponsored by the National Kidney Foundation and the US Food and Drug 
Administration. Am J Kidney Diseases 2009;54:205–26. 
[Mallinckrodt 2013] Mallinckrodt C, Roger J, Chuang-Stein C, Molenberghs G, Lane PW, 
O’Kelly M. Missing data: Turning guidance into action. Stat Biopharm Res 
2013;4:369-82. 
[O’Brien 2013] O’Brien E, Parati G, Stergiou G. Ambulatory blood pressure measurement 
- What is the international consensus. Hypertension 2013;62:988–94. 
[O’Neill 2012] O’Neill RT, Temple R. The prevention and treatment of missing data in 
clinical trials: an FDA perspective on the importance of dealing with it. Clin 
Pharmacol Ther 2012 Mar;91(3):550–4. 
[Ratitch 2013] Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from 
clinical assumptions to statistical analysis using pattern mixture models in SAS. 
Pharm Stat 2013;12:337–47. 
[Rubin 1987] Rubin DB. Multiple imputation for nonresponse in surveys. Wiley; 1987. 
[Strauss 1951] Strauss MB, Davis RK, Rosenbaum JD, Rossmeisl EC. Water diuresis 
produced during recumbency by the intravenous infusion of isotonic saline solution. 
J Clin Invest 1951;30:862-8. 
 
 


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14 APPENDICES 
14.1 Revision history 
Version Date 
Version 
Implemented Change(s) 
05-JUL-2018  
1.0 
Draft 1 
15-NOV-2018 
2.0 
Draft 2 
04-APR-2019 
1 
Final Version 1 
23-SEP-2021 
2 
• Section 1: Indicate protocol amendment and 
addendum related to the COVID-19 pandemic. 
• Section 2.1: Update added on the recruitment.  
• Section 2.4: Section added on the impact of the 
COVID-19 pandemic.  
• Section 4.1.6 and 4.17: Clarifications added on the 
PPS and mPSS sets. 
• Section 4.1.8 and 4.1.9: Clarifications added on the 
aFAS and maFAS sets. 
• Section 4.1.10 and 4.1.12: Actual treatment received 
definitions added for SAF and mSAF sets.  
• Section 4.1.13: Clarification added on the PK set. 
• Section 5.1.2 and 5.1.3: Summaries added for 
discontinuation reasons study/treatment related to the 
COVID-19 pandemic. 
• Section 5.2: Summaries added by study part for all 
PDs and important PDs and specific summaries 
related to the COVID-19 pandemic. 
• Section 5.3: Summary added for subjects excluded 
from the PK set.  
• Section 5.4.1: Region definition finalized based on 
final list of participating countries, BMI category 
added as a demographic variable. 
• Section 5.4.2: Clarification of the variables included 
in the disease characteristics.  
• Section 5.4.4: Clarifications added on the definitions 
of previous and concomitant therapy. 
• Section 5.5.1: Clarifications added for treatment 
duration calculation. 


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• Section 5.5.2: Calculation of compliance updated if 
bottle not returned. 
• Section 6.2.2: Clarifications added on the intercurrent 
events. 
• Section 6.2.4: Sensitivity analysis added for possible 
exclusion of site data. 
• Section 6.2.6: Added subgroups analyses for efficacy.  
• Section 6.2.7: Section added on the impact of 
COVID-19 pandemic on the analysis of primary 
endpoint. 
• Section 6.3.4: Sensitivity analysis added for possible 
exclusion of site data. 
• Section 6.3.7: Section added on the impact of 
COVID-19 pandemic on the analysis of key 
secondary endpoint. 
• Section 6.4.1: Clarification added on the ABPM valid 
reading specifications. 
• Section 6.5.2 and 6.5.3: Home SBP/DBP added as 
another efficacy endpoint to analyze. 
• Section 7.1.1.6: Section added for AESIs. 
• Section 7.4.2: Summary added for ECG findings. 
• Section 7.6.1: Clarification added on the definitions 
and exposure-adjusted MACE/MACE-plus incidence 
rates added. 
• Section 7.6.3: Updated analysis for biomarker. 
Biomarker analysis moved from efficacy 
(Section 6.8) to safety (Section 7.6.3).  
• Section 8.1: General rules for data presentation 
updated.  
• Section 10.1.2: Adjustment and clarification for time 
window added. 
• Section 10.2.2: Clarification added on the imputation 
rules. 
• Section 11: Explanation added on the changes from 
protocol. 
• Section 14: Definitions added in the appendices.  
06-APR-2022 
3 
• Section 1: Indicate the change of primary estimand 
following comments from regulatory agencies. 
• Section 4.1.6 and 4.1.7: Definitions update for PPS 
and mPPS.  
• Section 4.1.13: Clarifications added for PK set.  


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• Section 5.1.1: Clarifications on eligibility criteria 
summaries. 
• Section 5.4.1: Age and BMI categories adapted. Body 
weight category added. 
• Sections 5.4.2: Categorization added for number of 
antihypertensive therapies present at screening. 
• Section 5.4.4: Deletion of concomitant therapies 
summary present at baseline and descriptive table of 
individual antihypertensive therapies stopped or 
ongoing during screening period added. 
• Section 5.5.2: Interruptions moved from Section 5.1.3 
to 5.5.2 and additional details provided. 
• Section 6.2.2: Change of estimand strategy. 
• Section 6.2.4: Hypothetical strategy estimand will be 
used for sensitivity analysis. 
• Section 6.2.6: Subgroups updated or added.  
• Section 6.3.2: Change of estimand strategy. 
• Section 6.3.4: Hypothetical strategy estimand will be 
used for sensitivity analysis.  
• Section 6.3.6: Subgroups updated or added.  
• Section 6.5.1: BP control and response as exploratory 
endpoints.  
• Section 6.5.2: Addition of analysis specification for 
BP control and response. 
• Section 6.6: Update of table summary for efficacy 
analyses due to change of estimand strategy. 
• Section 7.1.2: Addition of analyses for time to (first) 
oedema/fluid retention. 
• Section 7.3.2: Addition of other thresholds for the 
marked abnormalities tables.  
• Section 8.2.2: Adjustment of code for multiple 
imputation.  
• Section 8.2.5: New code added for control/response 
endpoints.   
• Section 10.1.2: Time window changed and clarified.  
• Section 14.4:  Specifications added for 
antihypertensive medications.   
 


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14.2 Thresholds for marked abnormalities  
Parameter 
LL 
LLL 
HH 
HHH 
HHHH 
Hematology 
Hemoglobin  
< 100 g/L 
< 80 g/L 
Increase in > 20 g/L above 
ULN or above baseline if 
baseline is above ULN 
Increase in > 40 g/L above 
ULN or above baseline if 
baseline is above ULN 
 
Hematocrit 
< 28% in women  
< 32% in men 
< 20% 
> 55% in women 
> 60% in men 
> 65% 
 
Platelet count  
< 75 × 109/L 
< 50 × 109/L 
> 600× 109/L  
> 999× 109/L 
 
Leukocyte count 
< 3.0 × 109/L 
< 2.0 × 109/L 
> 20.0 × 109/L 
> 100.0 × 109/L 
 
Neutrophils  
< 1.5 × 109/L 
< 1.0 × 109/L  
NA 
NA 
 
Eosinophils 
NA 
NA 
> 5.0 × 109 
NA 
 
Lymphocytes 
< 0.8 × 109/L 
< 0.5 × 109/L 
> 4.0 × 109/L 
> 20 × 109/L 
 
Blood Chemistry 
AST (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
> 8 × 
ULN 
ALT (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
> 8 × 
ULN 
Alkaline 
Phosphatase 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 
 
Bilirubin Total 
(µmol/L) 
NA 
NA 
> 2 × ULN 
> 5 × ULN 
 
Creatinine  
NA 
NA 
> 1.5 × ULN 
or > 1.5 × baseline if 
baseline > ULN 
> 3 × ULN 
or > 3 × baseline if 
baseline > ULN 
 


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Parameter 
LL 
LLL 
HH 
HHH 
HHHH 
Glucose 
< 3.0 mmol /L 
< 2.2 mmol /L 
> 8.9 mmol /L 
> 13.9 mmol /L 
 
Sodium 
 
< 130 mmol/L 
> 150 mmol/L 
> 155 mmol/L 
 
Potassium 
< 3.2 mmol/L 
< 3.0 mmol/L 
> 5.5 mmol/L 
> 6.0 mmol/L 
 
Urate  
NA 
NA 
> 590 µmol/L 
> 720 µmol/L 
 
Albumin 
< 30 g/L 
< 20 g/L 
NA 
NA 
 
eGFR 
< 60 
mL/min/1.73m2 
< 30 
mL/min/1.73m2 
NA 
NA 
 
Cholesterol 
NA 
NA 
>7.76 mmol/L 
>10.34 mmol/L 
 
Triglyceride 
NA 
NA 
>1.69 mmol/L 
>3.39 mmol/L 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; NA = not applicable; ULN = upper limit of 
normal. 
Baseline = last assessment before randomization, also in the analysis of the DB-WD part. 
 


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14.3 Definition of adverse events of specific interest  
The SMQs are broad scope, unless stated otherwise. 
The definitions below are based on MedDRA version 24.1. 
Anaemia is defined as any AE within the “Haematopoietic erythropenia” SMQ or the 
“Haematopoietic cytopenias affecting more than one type of blood cell” SMQ, or it 
contains an event with any MedDRA Preferred Term containing the text “anaemia” (with 
the exception of the PT “Melanaemia”), or with the PT “Haemodilution”.  
Hepatic disorders are defined as any AE within the ‘Hepatic disorders’ SMQ. 
Oedema / fluid retention is defined as any AE within the SMQ “Haemodynamic oedema, 
effusions and fluid overload (SMQ)” or with the PTs Swelling of eyelid, Swelling face, 
Eyelid oedema, Face oedema.  
Decompensation/aggravation of heart failure is defined as any AE within the SMQ 
“Cardiac failure (narrow scope only)”. 


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14.4 Definition of diuretic and antihypertensives medications 
1. Diuretics = any medication with  
Anatomical Therapeutic Chemical class in 
(‘C03A’,’C03B’,’C03C’,’C03D’,’C03E’,’C03X’) or  
(‘C08GA’,’C09BA’,’C09DA’,’C07CA’,’C07CB’,’C07CG’,’C07DA’,’C07DB’) 
An addition/increase of diuretic is defined as increase if the dose of the existing 
diuretic (HCTZ) was increased after randomization or addition if a new diuretic was 
added.  
2. 
In order to derive the categories for the individual antihypertensive therapies stopped 
or ongoing during screening period the ATC names 2 to 4 are searched for the text 
strings listed below. The table is restricted for ATC1 class code =‘C’. 
 
Text string 
Class 
ACE INHIBITORS” 
Angiotensin-converting 
enzyme 
inhibitor (ACEi) 
ANGIOTENSIN II RECE” 
Angiotensin 
receptor 
blockers 
(ARB) 
CALCIUM CHANNEL BLOCK” 
Calcium channel blockers (CCB) 
DIURETICS” 
           - C03DA (ATC 4) 
Diuretics 
  - Mineralocorticoid Receptor 
Antagonist (MRA) 
BETA BLOCK” 
Beta-blockers 
CENTRALLY ACTING” 
Centrally 
acting 
antihypertensives 
‘OTHER COMBINATIONS’ in ATC4 only 
OTHERS IN COMBINATION 
If not in one of the above and ATC 2 
codes 
is 
in 
(‘C02’,’C03’,’C07’,’C08’,’C09’) 
OTHERS 
 
Note: if a text string contains multiple hits (e.g., “ANGIOTENSIN II RECEPTOR 
BLOCKERS (ARBS) AND DIURETICS”) each of them will be counted. 
For each subject, the number of antihypertensive therapies at screening will be derived as 
the number of distinct classes (e.g., if a subject has 2 different diuretics, this will be counted 
as only 1 medication). In addition, the class ‘OTHERS IN COMBINATION’ will count as 
2 medications (as this string is only used in ATC codes if there are more than 
2 components). 
 
 

Prot_001.pdf: 
Cover page 
Official Title: 
Multi-center, blinded, randomized, parallel-group, Phase 3 study with aprocitentan in 
subjects with resistant hypertension (RHT). 
ClinicalTrials.gov Identifier: 
NCT03541174 
Brief Title: 
A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to 
Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its 
Safety 
(PRECISION) 
Date of protocol addendum document: 
8 April 2020 


 
 
TPL-100601_v03 
 
 
 
 
 
 
 
ADDENDUM TO PROTOCOL 
ID-080A301 (PRECISION) 
Multi-center, blinded, randomized, PaRallEl-group, Phase 3 study with aproCItentan in 
Subjects with ResIstant HypertensiON (RHT) 
 
 
 
Exceptional measures to ensure subject safety and counteract 
potential trial conduct disruption due to the  
COVID-19 pandemic 
 
 
 
 
Document Number: D-20.063 
 
8 April 2020 
 
 
 
 
 
 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 
 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ........................................................... 3 
1 
INTRODUCTION ........................................................................................................ 4 
2 
RECOMMENDATIONS AND INSTRUCTIONS ...................................................... 4 
2.1 
Guidance on flexibility of study visits and safety assessments for 
subjects ongoing in the study ......................................................................... 4 
2.1.1 
Site visits for subjects who can still travel to the site ........................ 4 
2.1.2 
Conduct of remote visits for subjects who are not allowed or 
not willing to travel to the investigators site ...................................... 6 
2.2 
Provisions for subjects infected with SARS-CoV-2 ...................................... 8 
2.3 
Evaluation of primary efficacy endpoint ....................................................... 9 
2.3.1 
Efficacy / primary endpoint ............................................................... 9 
2.3.1.1 
Blood pressure analysis (primary and secondary 
endpoints) ................................................................................. 9 
2.3.1.2 
Impact on statistical analyses ................................................... 9 
2.4 
Reporting of protocol deviations related to the COVID-19 pandemic .......... 9 
2.5 
Monitoring ................................................................................................... 10 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
ALT 
 
Alanine aminotransferase 
AOBPM 
 
Automated office blood pressure measurement 
AST 
 
Aspartate aminotransferase 
BP 
 
Blood pressure 
COVID-19 
 
Coronavirus disease 2019 
CRA 
 
Clinical research associate 
GCP 
 
Good Clinical Practice 
eCRF 
 
Electronic case report form 
eGFR 
 
Estimated glomerular filtration rate 
EMA 
 
European Medicines Agency 
FDA 
 
Food and Drug Administration 
ICH 
 
International Council for Harmonisation 
IEC 
 
Independent ethics committee 
IFN 
 
Interferon 
IRB 
 
Institutional review board 
MCAR 
 
Missing completely at random  
NT-proBNP 
 
N-terminal pro-brain natriuretic peptide 
PD 
 
Protocol deviation 
SARS-CoV-2 
 
Severe acute respiratory syndrome coronavirus 2 
SBAT 
 
Standardized background antihypertensive therapy 
SDV 
 
Source data verification  
WHO 
 
World Health Organization 
 
 


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1 
INTRODUCTION 
As a consequence of the pandemic of respiratory infectious disease (COVID-19; declared 
a pandemic by the WHO on 11 March 2020) caused by a novel coronavirus 
(SARS-CoV-2), Idorsia provided instructions and guidance in communication letters sent 
to ID-080A301 (PRECISION) study investigators on 19 March 2020 and 31 March 2020. 
These measures and instructions are in line with health authority guidelines (FDA, EMA 
and individual national health authorities) released in March 2020 on how to address the 
challenges caused by the pandemic itself.  
These measures, which constitute PDs, are introduced to preserve subject safety, trial 
integrity and interpretability, as well as compliance with regulatory requirements. 
Idorsia tracks all these deviations from the protocol as “PDs related to COVID-19”. This 
will allow, at the end of the trial, a reconstruction of the impact that such deviations had on 
the trial integrity and interpretability. This requires that the instructions and measures 
included in this addendum continue to be collected as PDs as per original protocol 
definition, and will be identified as due to COVID-19 even after the implementation of this 
addendum. 
The objective of this addendum is to document those measures and instructions in the 
protocol. The addendum applies to those sites affected by the COVID-19 outbreak and 
is limited to the time during which such sites are affected.  
This addendum is therefore limited in scope and in duration.  
The recommendations and instructions that have been provided to the investigators are 
described below with reference to the protocol section(s) affected. 
2 
RECOMMENDATIONS AND INSTRUCTIONS 
New subjects may be considered for screening only after thorough evaluation of the risk-
benefit for the subject’s participation in the context of the COVID-19 pandemic. The 
Screening visit should only take place if a complete on-site visit can be organized. If this 
is not possible, the preferred option is to re-schedule the Screening visit at a time when all 
components of the site visit can be performed in full compliance with the protocol [see 
protocol section 7.1.1.1]. 
2.1 Guidance on flexibility of study visits and safety assessments for subjects 
ongoing in the study 
2.1.1 Site visits for subjects who can still travel to the site 
Ensure the subject’s safety on his/her way to the site by following local/country regulations 
(e.g., not using public transportation). Alternatively, subjects can use taxis or private cars, 
the cost of which will be reimbursed by Idorsia.  


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 Study visits, protocol section 7: On-site visits are the preferred option. If a site faces 
difficulty (e.g., limited site staff) scheduling visits according to the protocol, the visits 
can be re-scheduled with the provision that the subject has enough study medication, 
i.e., study treatment and SBAT. The reason for the delayed protocol visit (i.e., 
re-scheduling) must be documented in the subject’s medical chart. The instructions 
below are to be followed:  
 Screening period, protocol section 3.1.1.1: The flexibility is high as the protocol 
allows visits to be scheduled as needed. If it is not certain that the on-site visits can 
be performed in the near future, the subject can be discontinued and declared as a 
screen failure. Subjects who are screen failures due to COVID-19 can be re-
screened when it can be ensured that the study protocol can be followed again 
[protocol section 7.1.1.2]. This also applies to subjects who have already switched 
to the SBAT. 
 Run-in period, protocol section 3.1.1.2: Visit 3 can be skipped if it cannot be 
conducted. In addition, the duration of the run-in period can be between 3 and 
8 weeks based on the principal investigator’s judgment, by taking into 
consideration the subject’s medical conditions. 
 Double-blind part 1, protocol section 3.1.1.3: The key visits are Visit 4 
(Randomization) and Visit 6 (Week 4) as BP measurements collected during these 
two visits are needed to derive the study primary endpoint. The visit window for 
Visit 6 can be ±1 week. If this is not possible, the site staff should contact the Idorsia 
study team as soon as possible to evaluate potential alternatives.  
 Single-blind part 2, protocol section 3.1.1.3: The key visits are Visit 7 (Week 6) 
and Visit 11 (Week 36).  
o Visit 7 can be performed within a −2 days / +1 week window.  
o Visit 11 can be performed within a −12 days / +8 weeks window.  
o Other visits can be performed within a ±3 weeks window. 
 Due to the current circumstances, even more flexibility is allowed (e.g., 
skipping visits) based on the investigator’s judgment by taking into 
consideration a subject’s medical condition (e.g., BP level, ongoing adverse 
events).  
 Double-blind withdrawal part 3, protocol section 3.1.1.3: The key visits are 
Visit 13 (Re-randomization) and Visit 15 (Week 40) as BP measurements collected 
during these two visits are needed to derive the study key secondary endpoint. The 
visit window for these two visits can be ±1 week. If this is not possible, the Idorsia 
study team must be contacted as soon as possible to evaluate potential alternatives.  


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 Laboratory assessments, protocol section 7.2.3.5: If blood and urine samples cannot 
be collected by the courier for shipment to the central laboratory, site staff should make 
sure that, in addition to freezing the samples for delayed assessments, a portion of the 
sample is used to measure the following safety parameters by the site’s local laboratory: 
 Hemoglobin, NT-proBNP, serum creatinine, eGFR, ALT, AST, and total bilirubin.  
2.1.2 Conduct of remote visits for subjects who are not allowed or not willing to 
travel to the investigators site 
 Study visits, protocol section 7: As an alternative to an on-site visit, a telephone call 
or video call can be performed. Video call is the preferred option, if possible. A 
telephone call or video call does not replace an on-site visit. As soon as possible 
following the call, the corresponding on-site visit must be completed. If the 
(corresponding) on-site visit can only be scheduled relatively close to the next 
scheduled study visit (i.e., within 1 week of the next study visit), the corresponding 
study visit should be skipped and only the next scheduled study visit per protocol 
should be performed. 
1) Scheduling the call 
 When scheduling the date and time of the call, ensure that adequate time is planned to 
perform all the assessments listed below, including the risk-benefit evaluation for the 
subject regarding his/her continuation of study medications.  
 The subject should be asked to perform the following assessments on the day before 
the call:  
 BP measurements according to the protocol section 7.2.2.3 with the home BP 
device provided to her/him for the study, or, if not delivered, with her/his own BP 
device.  
 Body weight measurement according to protocol section 7.2.3.3.  
 Subject should be instructed to record the BP, body weight values and last study 
treatment/SBAT intake date and time in the home BP monitoring card or in a 
notebook. This will be the source document. 
2) During the call 
 Ask the subject for the measured BP and body weight values and record them in the 
subject’s medical chart. 
 Remind the subject to bring the home BP monitoring card or the notebook to the 
next on-site visit for verification.  
 Ask for adverse events, follow the same process as for site visit, i.e., use an open-ended 
question such as: “Have you had any medical problem since the last study visit?” 


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 Ask whether any new medication has been taken or other medication has been 
modified.  
 Study treatment, protocol section 5:  
 Remind the subject about the importance of taking study medications according to 
the protocol. 
 Check if the subject has enough study treatment and SBAT to ensure no study 
treatment and/or SBAT holiday. If the subject does not have enough study treatment 
and/or SBAT to last until the next visit, follow the instructions below:  
o If possible, the subject or a relative can collect study treatment and/or SBAT 
from the site (e.g., at a specific site delivery point / at the gate of the clinic).  
o If the above option is not possible, study treatment and/or SBAT may be sent 
to the subject’s home using a local courier organized by site or through the site’s 
CRA.  
o If neither of the above options are possible, the site’s CRA is to be contacted. 
Idorsia will support the site and the CRA to find the best solution for the subject 
(e.g., collect SBAT from the local pharmacy).  
 Laboratory assessments, protocol section 7.2.3.5:  
 For subjects with a medical history of heart disease and/or fluid retention/edema, 
ongoing adverse events related to cardiovascular diseases, or eGFR between 15 and 
30 mL/min/1.73 m2, the following blood parameters must be measured: 
hemoglobin, NT-proBNP, serum creatinine, eGFR, ALT, AST, and total bilirubin.  
o If a subject is allowed to leave the house according to the local regulations, 
assist him/her to find a local laboratory close to his/her home for the above 
measurements. Provide a prescription for the tests to be performed. Costs 
incurred will be reimbursed by Idorsia.  
o If a subject is not allowed to leave the house according to the current local 
regulations, organize the drawing of blood samples at the subject’s home. In the 
event of difficulties, the site’s CRA can be contacted for support.  
o Ask the subject to report back to the site as soon as results are received and to 
keep the local laboratory report. This will be used as the source document and 
must be given to the site at the next visit.  
o If neither of the above options are possible, a thorough risk-benefit evaluation 
of the treatment and the study in the COVID-19 context must be performed to 
decide whether this subject should remain in the study.  


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 For women of childbearing potential: make sure the subject has enough home urine 
pregnancy kits (send them along with study medications to subject’s home if 
necessary), remind them to perform the test monthly and ask for results. 
 Data collection, protocol section 11.1: The telephone or video contact must be entered 
as an unscheduled visit in the eCRF and documented in detail (date, time and 
conversation) in the subject’s medical charts. 
 Informed consent, protocol section 12.3: If study treatment, SBAT and/or pregnancy 
kits need to be shipped to subject’s home, ensure the following:  
 Obtain the subject’s verbal consent by telephone to provide his/her name and home 
address to the courier service responsible for delivering study medications and 
pregnancy test. The date and time that verbal consent was obtained must be 
documented in the subject’s medical records.  
 If, according to your local regulation, the subject’s consent must be in writing, act 
accordingly (e.g., request consent by email) and document it in the subject’s 
medical charts. 
2.2 Provisions for subjects infected with SARS-CoV-2 
Testing for SARS-CoV-2 should follow local guidance. Mandatory testing is not requested 
for this study. Should a subject become infected with SARS-CoV-2:  
 Information about positivity for SARS-CoV-2 and its corresponding diagnosis 
(symptoms) as well as administered medications will be collected on the Adverse 
Events and Concomitant Medication pages of the eCRF.  
 If a subject becomes infected, study treatment should be continued as there is no reason 
to believe that aprocitentan could have a negative impact on SARS-CoV-2 infection or 
its complications. In addition, abruptly stopping a potentially active treatment may 
destabilize the control of BP and contribute to a worse prognosis in the event of 
COVID-19. This also applies to the SBAT: “EMA advises continued use of medicines 
for hypertension, heart or kidney disease during COVID-19 pandemic” 
(EMA/143324/2020). 
 In the event of infection with SARS-CoV-2, on the basis of our current knowledge, a 
subject can be treated with the currently available most frequently used medications for 
COVID-19 (e.g., remdesivir, lopinavir/ritonavir, IFN beta1b, corticosteroids, 
hydroxychloroquine) given that aprocitentan and the anti-COVID-19 drugs are not 
expected to mutually affect their pharmacokinetic or pharmacodynamic properties 
based on an effect on metabolizing enzymes or transporters. The full description of 
potential drug-drug interactions with aprocitentan is provided the Investigator’s 
Brochure.  


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 When shipping samples from subjects who tested positive or had high potential to test 
positive for SARS-CoV-2 virus infection to the study central laboratory, the central 
laboratory manual and the most updated COVID-19 regional guidance provided by 
Q Squared Solutions should be followed. 
2.3 Evaluation of primary efficacy endpoint 
2.3.1 Efficacy / primary endpoint 
It is expected that investigators will not be able to perform all on-site visits while the site 
is affected by the COVID-19 pandemic. 
2.3.1.1 Blood pressure analysis (primary and secondary endpoints) 
The primary and key secondary efficacy endpoints of this study need to be measured at 
on-site visits (i.e., at Visits 4, 6, 11 and 13) with an unattended AOBPM device [see 
protocol sections 6.1.1 and 6.1.2]. If these measurements cannot be performed due to 
missing on-site visits because of the COVID-19 pandemic, the BP should be measured at 
home [see Section 2.1.2]. 
2.3.1.2 Impact on statistical analyses 
It is expected that the amount of missing data will increase due to the COVID-19 pandemic. 
Missing data due to missed on-site visits are assumed to be MCAR. Thus, data missing due 
to the COVID-19 pandemic should not introduce bias in the statistical analyses.  
The analysis of the primary endpoint [protocol section 10.3.2] is based on AOBPM data 
collected at Randomization (Visit 4) and Week 4 (Visit 6). Data missing because of on-site 
Visits 4 and 6 were missed due to the COVID-19 pandemic will not be imputed but will be 
handled by the mixed model specified for the primary endpoint analysis.  
The analysis of the key secondary endpoint [protocol section 10.3.3] is based on AOBPM 
data collected at Re-randomization (Visit 11) and Week 40 (Visit 13). Data missing 
because on-site Visits 11 and 13 were missed due to the COVID-19 pandemic will be 
handled by the mixed model specified for the key secondary endpoint analysis. 
If the amount of missing AOBPM data at Visits 4, 6, 11 and 13 due to the COVID-19 
pandemic is high (e.g., double the expectations in the protocol), home BP values may be 
included in the main analysis of the primary and/or key secondary endpoints. The home 
BP values will in any case be included in a supportive analysis. This will be described in 
an update of the statistical analysis plan. 
2.4 Reporting of protocol deviations related to the COVID-19 pandemic 
PDs due to COVID-19 are expected to occur during the pandemic and fall under ICH GCP 
section 4.5.4: “The investigator may implement a deviation from, or change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects”. Any PD occurring due to COVID-19 
must be documented according to ICH GCP section 4.5.3 and clearly recorded as related 


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to COVID-19. All PDs will be reported to the sponsor, IEC/IRB and regulatory authorities 
according to local requirements.  
2.5 Monitoring 
If on-site monitoring cannot be performed by the CRA as described in protocol 
section 12.8, and if acceptable under local law with the IEC/IRB, the CRA will conduct 
remote monitoring and remote SDV, provided that subject confidentiality is maintained 
throughout the process [as per protocol section 11.2] and all local approvals to do so are in 
place. If remote monitoring or remote SDV are not allowed, alternatives as applicable 
according to local regulations might be agreed with the principal investigator to ensure data 
integrity.  

Prot_000.pdf: 
Cover page 
 
 
Official Title: 
Multi-center, blinded, randomized, parallel-group, Phase 3 study with aprocitentan in 
subjects with resistant hypertension (RHT). 
ClinicalTrials.gov Identifier: 
NCT03541174 
 
 
Brief Title: 
A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to 
Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its 
Safety  
(PRECISION) 
 
Date of protocol document: 
27 February 2020 


TPL-100601_v01 
Aprocitentan / ACT-132577 
Resistant Hypertension 
Protocol ID-080A301 
PRECISION 
Multi-center, blinded, randomized, PaRallEl-group, Phase 3 study with aproCItentan in 
Subjects with ResIstant HypertensiON (RHT) 
Study Phase: 
3 
EudraCT Number: 
2017-004393-33 
Status and version: 
Final Version 3 
Date: 
27 February 2020 
Document type: 
Amended global protocol 
Idorsia document number 
(Doc No.): 
D-20.008
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Idorsia Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your personnel, and an independent ethics committee 
or institutional review board. It is understood that this information will not be disclosed to others without 
written authorization from Idorsia Pharmaceuticals Ltd, except to the extent necessary to obtain informed 
consent from those persons to whom the study treatment may be administered. 


Aprocitentan / ACT-132577 
Resistant hypertension 
Protocol ID-080A301 
Version 3 
27 February 2020, page 2/117 
Confidential 
EudraCT 2017-004393-33 
Doc No D-20.008 
SPONSOR CONTACT DETAILS 
Sponsor 
Idorsia Pharmaceuticals Ltd 
Hegenheimermattweg 91 
CH-4123 Allschwil 
Switzerland 

+41 58 844 00 00
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File. 
Medical Emergency Hotline 
Toll phone number:  
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File. 
CONTRACT RESEARCH ORGANIZATIONS’ INFORMATION 
Some study activities will be delegated to Contract Research Organizations (CROs). A 
list of site-specific contact details can be found in the Investigator Site File. 


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SIGNATURE PAGE FOR IDORSIA PHARMACEUTICALS LTD 
Hereinafter called Idorsia or sponsor 
Treatment name/ number 
Aprocitentan / ACT-132577 
Indication 
Resistant hypertension 
Protocol number, study acronym, study title 
ID-080A301, PRECISION 
Multi-center, blinded, randomized, parallel-group, Phase 3 study with aprocitentan in 
subjects with resistant hype1iension (RHT). 
I approve the te1ms and conditions relating to this study as defined in this protocol. I 
confnm that the infonnation contained in this protocol is consistent with the cm-rent 
risk-benefit evaluation of aprocitentan, and with the ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and the International 
Council for Haimonisation (ICH) Good Clinical Practice (GCP) guidelines. 
Title 
Name 
Date 
PPD 
Signature 
=p=p=oc-'
PPD 
-=======-- -


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Resistant hypertension 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Aprocitentan / ACT-132577 
Indication 
Resistant hypertension  
Protocol number, study acronym, study title 
ID-080A301, PRECISION, 
Multi-center, blinded, randomized, parallel-group, Phase 3 study with aprocitentan in 
subjects with resistant hypertension (RHT). 
I agree to the terms and conditions relating to this study as defined in this protocol and any 
other protocol-related documents. I fully understand that any changes instituted by the 
investigator(s) without previous agreement with the sponsor would constitute a protocol 
deviation, including any ancillary studies or procedures performed on study subjects (other 
than those procedures necessary for the wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. 
Country 
Site 
number 
Town 
Date 
Signature 
Principal 
Investigator 


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Doc No D-20.008 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................12 
SUBSTANTIAL GLOBAL AMENDMENT 2 .................................................................16 
PROTOCOL SYNOPSIS ID-080A301 .............................................................................21 
PROTOCOL ......................................................................................................................32 
1 
BACKGROUND .........................................................................................................32 
1.1 
Hypertension and resistant hypertension ......................................................32 
1.1.1 
Current treatment of RHT .................................................................33 
1.1.2 
Unmet medical need in RHT ............................................................34 
1.2 
Aprocitentan .................................................................................................34 
1.2.1 
Mechanism of action and rationale for development in RHT ..........34 
1.2.2 
Nonclinical summary ........................................................................35 
1.2.3 
Clinical summary ..............................................................................35 
1.2.4 
Aprocitentan dose rationale ..............................................................39 
1.3 
Rationale of the study ...................................................................................40 
1.4 
Summary of known and potential risks and benefits ....................................40 
2 
STUDY OBJECTIVES ...............................................................................................41 
2.1 
Primary objective ..........................................................................................41 
2.2 
Secondary objectives ....................................................................................41 
2.3 
Other objectives ............................................................................................42 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................42 
3.1 
Study design .................................................................................................42 
3.1.1 
Study periods ....................................................................................42 
3.1.1.1 
Screening period ..................................................................... 43 
3.1.1.2 
Placebo run-in period ............................................................. 43 
3.1.1.3 
Randomized treatment period ................................................ 43 
3.1.1.4 
Safety follow-up (FU) period ................................................. 44 
3.1.2 
Study duration ...................................................................................45 
3.2 
Overall study design rationale ......................................................................45 
3.2.1 
Rationale for DB part ........................................................................45 
3.2.2 
Rationale for SB aprocitentan part and DB-WD part .......................46 
3.3 
Study committees .........................................................................................46 
3.3.1 
Independent Central Adjudication Committee .................................46 


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3.3.2 
Independent Data Monitoring Committee ........................................46 
4 
STUDY POPULATION .............................................................................................47 
4.1 
Selection of study population .......................................................................47 
4.2 
Rationale for the selection of the study population ......................................48 
4.3 
Inclusion criteria ...........................................................................................48 
4.4 
Exclusion criteria ..........................................................................................49 
4.5 
Criteria for women of childbearing potential ...............................................51 
4.5.1 
Definition of childbearing potential ..................................................51 
4.5.2 
Acceptable methods of contraception ...............................................52 
5 
TREATMENTS ..........................................................................................................54 
5.1 
Study treatment .............................................................................................54 
5.1.1 
Investigational treatment and matching placebo ..............................54 
5.1.2 
Study treatment dosing and rationale ................................................54 
5.1.3 
Study treatment administration .........................................................54 
5.1.4 
Treatment assignment .......................................................................54 
5.1.5 
Blinding ............................................................................................55 
5.1.6 
Unblinding ........................................................................................56 
5.1.6.1 
Unblinding for final analyses ................................................. 56 
5.1.6.2 
Unblinding for suspected unexpected serious adverse 
reactions .................................................................................. 56 
5.1.6.3 
Emergency procedure for unblinding ..................................... 56 
5.1.7 
Study treatment supply .....................................................................56 
5.1.7.1 
Study treatment packaging and labeling ................................ 57 
5.1.7.2 
Study treatment distribution and storage ................................ 57 
5.1.7.3 
Study treatment dispensing .................................................... 57 
5.1.7.4 
Study treatment return and destruction .................................. 57 
5.1.8 
Study treatment adherence ................................................................57 
5.1.8.1 
Study treatment adherence based on accountability ............... 58 
5.1.8.2 
Standardized background antihypertensive therapy 
adherence based on urine analysis .......................................... 59 
5.1.9 
Study treatment dose adjustments and interruptions ........................59 
5.1.10 
Premature discontinuation of study treatment ..................................60 
5.1.11 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................61 
5.1.11.1 
Hypertension .......................................................................... 61 
5.1.11.2 
Renal failure ........................................................................... 61 
5.1.11.3 
Persistent fluid retention ......................................................... 61 
5.1.11.4 
Hemoglobin abnormalities ..................................................... 61 


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5.1.11.5 
Liver aminotransferases abnormalities ................................... 62 
5.1.11.6 
Pregnancy ............................................................................... 63 
5.2 
Previous and concomitant therapy ................................................................63 
5.2.1 
Definitions ........................................................................................63 
5.2.2 
Mandatory concomitant therapy .......................................................63 
5.2.3 
Allowed concomitant therapy ...........................................................64 
5.2.3.1 
Antihypertensive rescue medication ...................................... 65 
5.2.3.2 
Diuretics for fluid retention .................................................... 65 
5.2.4 
Forbidden concomitant therapy ........................................................65 
5.2.5 
Reporting of previous / concomitant therapy in the eCRF ...............66 
5.2.5.1 
Antihypertensive therapies ..................................................... 66 
5.2.5.2 
Other therapies ....................................................................... 66 
6 
STUDY ENDPOINTS ................................................................................................66 
6.1 
Efficacy endpoints ........................................................................................66 
6.1.1 
Primary efficacy endpoint .................................................................66 
6.1.2 
Secondary efficacy endpoints ...........................................................67 
6.1.3 
Other efficacy endpoints ...................................................................67 
6.2 
Safety endpoints ...........................................................................................67 
6.3 
Pharmacokinetic endpoints ...........................................................................68 
6.4 
Biomarker endpoints .....................................................................................68 
6.5 
Rationale for primary and secondary endpoints ...........................................68 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................69 
7.1 
Study visits ...................................................................................................69 
7.1.1 
Screening/re-screening ......................................................................69 
7.1.1.1 
Screening ................................................................................ 69 
7.1.1.2 
Re-screening ........................................................................... 69 
7.1.2 
Placebo RI period ..............................................................................70 
7.1.3 
Randomized treatment period ...........................................................70 
7.1.4 
Unscheduled visits ............................................................................70 
7.2 
Study assessments .........................................................................................75 
7.2.1 
Baseline demographics and disease characteristics ..........................76 
7.2.1.1 
Hypertension history .............................................................. 76 
7.2.1.2 
Data to be collected for screening failure subjects ................. 76 
7.2.2 
Efficacy assessments .........................................................................76 
7.2.2.1 
Unattended automated office blood pressure 
measurement (AOBPM) ......................................................... 76 
7.2.2.2 
Ambulatory blood pressure monitoring ................................. 77 
7.2.2.3 
Home blood pressure measurement ....................................... 78 


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7.2.3 
Safety assessments ............................................................................78 
7.2.3.1 
Vital signs ............................................................................... 79 
7.2.3.2 
Physical examination .............................................................. 79 
7.2.3.3 
Weight and height .................................................................. 79 
7.2.3.4 
ECG assessment ..................................................................... 80 
7.2.3.5 
Laboratory assessments .......................................................... 80 
7.2.4 
Pharmacokinetic assessments ...........................................................83 
7.2.4.1 
Sampling, labeling, storage and shipment .............................. 83 
7.2.4.2 
Bioanalysis ............................................................................. 83 
7.2.5 
Biomarker assessments .....................................................................84 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................84 
8.1 
Study completion as per protocol .................................................................84 
8.2 
Premature withdrawal from study ................................................................84 
8.3 
Premature termination or suspension of the study ........................................85 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................86 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................86 
9.1 
Safety definitions ..........................................................................................86 
9.1.1 
Definition of adverse events .............................................................86 
9.1.2 
Definition of serious adverse events .................................................87 
9.1.3 
Definition of suspected unexpected serious adverse reaction ..........87 
9.1.4 
Definition of the intensity of adverse events ....................................88 
9.1.5 
Relationship to study treatment ........................................................88 
9.1.6 
Relationship to study design or protocol-mandated procedure ........88 
9.2 
Time period and frequency for AE/SAE assessment and follow-up ............88 
9.2.1 
Follow-up of adverse events .............................................................89 
9.2.2 
Follow-up of serious adverse events .................................................89 
9.3 
Reporting procedures ....................................................................................89 
9.3.1 
Reporting of adverse events ..............................................................89 
9.3.2 
Additional reporting procedures for serious adverse events .............89 
9.3.3 
Additional reporting procedures for SUSAR ....................................90 
9.4 
Pregnancy .....................................................................................................90 
9.4.1 
Reporting of pregnancy ....................................................................90 
9.4.2 
Follow-up of pregnancy ....................................................................90 
9.5 
Reporting of study treatment overdose, misuse, and abuse ..........................91 
9.6 
Study safety monitoring ................................................................................91 


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10 STATISTICAL METHODS .......................................................................................91 
10.1 
Analysis sets .................................................................................................91 
10.1.1 
Screened Set ......................................................................................91 
10.1.2 
Run-in Set .........................................................................................91 
10.1.3 
Full Analysis Set (FAS) ....................................................................91 
10.1.4 
Per Protocol Set ................................................................................92 
10.1.5 
Modified FAS ...................................................................................92 
10.1.6 
ABPM FAS .......................................................................................92 
10.1.7 
Modified ABPM FAS .......................................................................92 
10.1.8 
Safety Analysis Set ...........................................................................92 
10.1.9 
Modified Safety Analysis Set ...........................................................92 
10.1.10 
Pharmacokinetic Set .........................................................................92 
10.1.11 
Usage of the analysis sets .................................................................92 
10.2 
Variables .......................................................................................................93 
10.2.1 
Primary efficacy variable ..................................................................93 
10.2.2 
Secondary efficacy variables ............................................................93 
10.2.3 
Safety variables .................................................................................93 
10.3 
Description of statistical analyses .................................................................94 
10.3.1 
Overall testing strategy .....................................................................94 
10.3.2 
Analysis of the primary efficacy variable .........................................94 
10.3.2.1 
Main analysis in the DB part .................................................. 95 
10.3.2.2 
Handling of missing data in the DB part ................................ 95 
10.3.2.3 
Sensitivity analyses for missing data in the DB part .............. 95 
10.3.2.4 
Supportive analyses in the DB part ........................................ 96 
10.3.2.5 
Subgroup analyses in the DB part .......................................... 96 
10.3.3 
Analysis of the key secondary efficacy variable ..............................96 
10.3.3.1 
Main analysis in the DB-WD part .......................................... 97 
10.3.3.2 
Handling of missing data in the DB-WD part ........................ 97 
10.3.3.3 
Sensitivity analyses for missing data in the DB-WD part ...... 97 
10.3.3.4 
Supportive analyses in the DB-WD part ................................ 97 
10.3.3.5 
Subgroup analyses in the DB-WD part .................................. 98 
10.3.4 
Analysis of the other secondary efficacy variables ..........................98 
10.3.5 
Analysis of other efficacy variables ..................................................98 
10.3.6 
Analysis of the safety variables ........................................................98 
10.3.6.1 
Adverse events ....................................................................... 98 
10.3.6.2 
Laboratory data ....................................................................... 99 
10.3.6.3 
Vital signs ............................................................................... 99 
10.3.6.4 
ECG ...................................................................................... 100 
10.3.6.5 
Treatment-emergent MACE and MACE-plus ..................... 100 


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10.3.6.6 
Increase in dose of existing diuretic or addition of new 
diuretic due to fluid retention ............................................... 100 
10.3.7 
Analysis of other variables .............................................................100 
10.4 
Interim analyses ..........................................................................................100 
10.5 
Sample size .................................................................................................100 
11 DATA HANDLING ..................................................................................................101 
11.1 
Data collection ............................................................................................101 
11.2 
Maintenance of data confidentiality ...........................................................102 
11.3 
Database management ................................................................................102 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................103 
12.1 
Ethics and Good Clinical Practice ..............................................................103 
12.2 
Independent Ethics Committee / Institutional Review Board 
(IEC/IRB) ...................................................................................................103 
12.3 
Informed consent ........................................................................................103 
12.4 
Compensation to subjects and investigators ...............................................104 
12.5 
Protocol adherence/compliance ..................................................................104 
12.6 
Protocol amendments .................................................................................104 
12.7 
Essential documents and retention of documents .......................................105 
12.8 
Monitoring ..................................................................................................106 
12.9 
Investigator Site File ...................................................................................107 
12.10 
Audit ...........................................................................................................107 
12.11 
Inspections ..................................................................................................107 
12.12 
Reporting of study results and publication .................................................108 
13 REFERENCES ..........................................................................................................109 
14 APPENDICES ...........................................................................................................116 
 


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LIST OF TABLES 
 
Table 1 
BP thresholds for the definition of uncontrolled BP (i.e., 
hypertension) ............................................................................................. 47 
Table 2 
Visit and assessment schedule up to randomization ................................. 71 
Table 3 
Visit and assessment schedule from start of DB Treatment period up 
to EOS ....................................................................................................... 73 
Table 4 
Role of the analysis sets ............................................................................ 93 
Table 5 
Power to detect a treatment difference for the primary endpoint ............ 101 
 
LIST OF FIGURES 
 
Figure 1 
Study design .............................................................................................. 42 
 
LIST OF APPENDICES 
 
Appendix 1 
Forbidden drugs ....................................................................................... 116 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
ABPM 
Ambulatory blood pressure monitoring 
ACEI 
Angiotensin-converting enzyme inhibitor 
AE 
Adverse event 
aFAS 
ABPM Full Analysis Set 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AOBPM 
Automated office blood pressure measurement 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
bpm 
Beats per minute 
CAC 
Central Adjudication Committee 
CCB 
Calcium channel blocker 
CI 
Confidence interval 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease-Epidemiology  
CR 
Copy Reference 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTT 
Clinical Trial Team 
CYP3A4 
Cytochrome P450 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
DDI 
Drug-drug interaction 
DM 
Diabetes mellitus 
DOT 
Direct observed treatment 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form  
eGFR 
Estimated glomerular filtration rate 
EOS 
End-of-Study 


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EOT 
End-of-Treatment 
ERA 
Endothelin receptor antagonist 
ESC 
European Society of Cardiology 
ESH 
European Society of Hypertension 
ET 
Endothelin 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
HCTZ 
Hydrochlorothiazide 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISAC 
Independent Statistical Analysis Center  
ISF 
Investigator Site File 
J2R 
Jump to Reference 
LSM 
Least Squares Mean 
MACE 
Major adverse cardiac event(s) 
maFAS 
Modified ABPM Full Analysis Set 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified Full Analysis Set 
MI 
Myocardial infarction 


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MNAR 
Missing not at random 
MRA 
Mineralocorticoid receptor antagonist 
MR-proANP 
Mid-regional pro-atrial natriuretic peptide 
mSAF 
Modified Safety Analysis Set 
NT-proBNP 
N-terminal pro-brain natriuretic peptide
NYHA 
New York Heart Association
PD 
Pharmacodynamic(s)
PI 
Principal Investigator
PK 
Pharmacokinetic(s)
PPS 
Per Protocol Set
QS 
Quality System
QTc 
Corrected QT
QTcB 
QT corrected according to Bazett’s formula
QTcF 
QT corrected according to Fridericia’s formula
RAS 
Renin angiotensin system
RHT 
Resistant hypertension
RI 
Run-in
RIS 
Run-in Set
RSI 
Reference safety information
SAE 
Serious adverse event
SAF 
Safety Analysis Set
SAP 
Statistical Analysis Plan
SB 
Single-blind
SBP 
Systolic blood pressure
SCR 
Screened Set
SiDBP 
Sitting diastolic blood pressure
SiSBP 
Sitting systolic blood pressure
SIV 
Site initiation visit
SOC 
System organ class
SSRI 
Selective serotonin reuptake inhibitor
SUSAR 
Suspected unexpected serious adverse reaction


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UACR 
Urine albumin-to-creatinine ratio 
ULN 
Upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
WD 
Withdrawal 
WHO 
World Health Organization 


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SUBSTANTIAL GLOBAL AMENDMENT 2 
Amendment rationale 
This global amendment applies to the global protocol ID-080A301 Version 2 dated 
19 September 2018. The resulting amended global protocol is Version 3 dated 
27 February 2020.  
The main changes to the protocol in this amendment are: 
1. The inclusion criteria 4 and 11, section 4.3.
2. The exclusion criteria 5 and 11, section 4.4.
3. The study-specific discontinuation criterion for renal failure, section 5.1.11.2.
4. The forbidden medication, appendix 1.
The changes are as follows:
1. The inclusion criteria 4 and 11 have been modified (strikethrough and/or bold) to:
1a: Inclusion criterion 4:

Treated with at least 3 antihypertensive therapies of different pharmacological
classes including a diuretic for at least 4 weeks before the screening visit (Visit 1).
Beta blockers are not counted as background antihypertensive medication.
This criterion was previously selected in line with recent hypertension guidelines (e.g., 
ESH 2018 [Williams 2018], AHA [Whelton 2017] which recommends a diuretic as one of 
the 3 background antihypertensive medications, and beta-blockers mainly as the 4th 
medication or earlier (e.g., as the 2nd or 3rd medication) if it is prescribed for other 
indications than hypertension (e.g., heart failure, angina, post-myocardial infarction, atrial 
fibrillation).  
Information collected during the screening period in PRECISION show that some subjects 
are not treated with a diuretic and/or that a beta-blocker is used as an antihypertensive 
medication. Therefore, to open the recruitment for those patients who have uncontrolled 
blood pressure (BP) but are treated with a combination of medications that are not strictly 
aligned to the recent hypertension guidelines, this inclusion criterion was modified. 
This modification will not affect the intended patient population in this study which 
remains true resistant hypertension (RHT). The management of the subjects as per current 
Version 2 of the protocol beyond screening is not altered as the background 
antihypertensive medications of all screened subjects will be standardized by switching to 
a fixed-dose combination of a calcium channel blocker (CCB; amlodipine), an angiotensin 


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receptor blocker (ARB; valsartan) and a diuretic (hydrochlorothiazide [HCTZ]) for at least 
2 months prior to randomization. Subjects who are treated with a beta-blocker at screening 
will continue to receive the same beta-blocker therapy, in addition to the standardized 
fixed-dose combination therapy. Subjects will have to have uncontrolled BP (i.e., mean 
trough sitting systolic blood pressure [SiSBP] ≥ 140 mmHg measured by automated office 
blood pressure measurement [AOBPM]) despite treatment with 3 antihypertensive 
medications including a diuretic (in line with the guidelines’ recommendation) to continue 
in the study and enter the run-in period.  
1b: Inclusion criterion 11: 

Stable dose of the standardized background antihypertensive therapy since the start
for at least 1 week before Day –1 (end of the RI period).
This inclusion criterion was previously put in place to ensure a stable dose of the 
standardized background antihypertensive therapy and consequently a stable blood 
pressure before randomization.  
The standardized background antihypertensive therapy is a triple fixed-dose combination 
of amlodipine, valsartan and HCTZ. Two dose strengths will be available: 10/160/25 and 
5/160/25 mg (amlodipine, valsartan, HCTZ, respectively) to account for potential edema 
which occurs in a dose-related manner with amlodipine. The protocol recommends use of 
amlodipine 10 mg (section 5.2.2). Consequently, for subjects having tolerability issues 
with the higher dose of 10 mg the lower dose of 5 mg can be used.  
This modification will not affect the intended patient population and or jeopardize the study 
results since according to the amlodipine United States Prescribing Information (USPI) 
patient’s response to each dose level of amlodipine is achieved over 7 to 14 days.  
2. The screening exclusion criteria 5 and 11 have been extended (bold) to:
2a: Exclusion criterion 5:

Clinically significant unstable cardiac disease at screening or in the past in the
opinion of the investigator, e.g., uncontrolled symptomatic arrhythmia, atrial
fibrillation, congestive heart failure NYHA stage II with relevant mitral valve
insufficiency and/or aortic stenosis, congestive heart failure NYHA stage III or
IV, congestive heart failure.
This criterion excludes subjects with significant or potential unstable cardiac disease. 
During the medical review of enrolled subjects, it was noticed that some subjects entered 
the study with New York Heart Association (NYHA) stage II. However, their medical 
history suggested possible instability in their cardiac condition due to mitral valve 
insufficiency and/or aortic stenosis. Therefore, further explanation was added to the 


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criterion to exclude subjects with clinically significant unstable cardiac conditions to be 
entered into this study. This modification will not affect the intended patient population in 
this study. It emphasizes exclusion of subjects with clinically significant unstable cardiac 
disease. 
2b: Exclusion criterion 11: 

Treatment with any medication which may affect BP (e.g., treatment of psychiatric
diseases) [see Appendix 1] and/or treatment with high dose of loop diuretics
(i.e., furosemide greater than 80 mg/day, or equivalent dosage of other loop
diuretics).
The third Independent Data Monitoring Committee (IDMC) meeting took place on 
3 February 2020. The IDMC recommends continuing the study as planned without 
modification, however there was one subject with cardiac failure with preserved ejection 
fraction (NYHA stage II), post procedural pulmonary embolism and diabetes mellitus type 
2 who entered the study receiving background antihypertensive medications from different 
pharmacological classes including the following diuretics: high dose of loop diuretics (i.e., 
furosemide 80 mg twice a day) and thiazide diuretic (i.e., hydrochlorothiazide 25 mg). 
These background antihypertensive medications were switched to the standardized 
background antihypertensive therapy (i.e., triple fixed-dose combination of amlodipine, 
valsartan and hydrochlorothiazide) according to the protocol. High dose of loop diuretics 
is normally prescribed for treatment of congestive heart failure (an exclusion criterion for 
this study, see section 4.4, exclusion criterion 5) and its modification might destabilize 
clinical conditions of a subject. Therefore, further explanation was added to the criterion 
to emphasize subjects treated with high dose of loop diuretics are not suitable for this study. 
3. The second component of the study-specific discontinuation criterion for renal failure
has been modified to:

Confirmed (within one week) decrease increase of ≥ 30% > 2  from baseline in
eGFR based on the CKD EPI equation serum creatinine.
This discontinuation criterion was previously based on estimated glomerular filtration rate 
(eGFR), since eGFR is a biomarker for renal function. However, a decline in eGFR might 
be related only to hemodynamic modifications as observed with other antihypertensive 
therapies, such as renin angiotensin blockers [Palmer 2002] and not secondary to structural 
kidney injury. The BP decrease induces a reduction of the intraglomerular pressure which 
impacts the eGFR. Endothelin receptor antagonist indeed induces vasodilation on the 
afferent and efferent intra-glomerular arterioles with presumably a more pronounced effect 
on the efferent one [Kohan 2011]. Therefore, to avoid discontinuation of subjects due to 
potentially transient eGFR reduction this criterion was modified. The new criterion is using 
serum creatinine change. Serum creatinine is less influenced by hemodynamic 


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modifications and reflects more organ damage of the kidney. This is in line with the Acute 
Kidney Injury score [Kellum 2013] which is based on serum creatinine level. This ensures 
appropriate monitoring and discontinuation of subjects at risk of potential kidney injury.  
4. Changes of forbidden medication, appendix 1.

Removal of erythropoiesis-stimulating agents and psychiatric drugs from the list of the
forbidden medications and adding them to allowed medications with the provision that
they have been initiated and the dose has been stable at least 4 weeks prior to the
screening visit, and that the dose is kept stable until the end of treatment.
Information collected during the screening period in PRECISION shows subjects who 
cannot enter the study because they are treated with these medications. Since it is not 
expected that stable dose of these medications will impact the BP analysis, these 
medications were removed from the list of forbidden medications. In addition for 
completeness, the topical medications allowed are more exhaustively described. 
Additional changes have been made to: 

Exclusion criterion 15 in section 4.4: removal of “planned treatment”.

Clarify and provide the definition for overdose, abuse, and misuse in section 9.5.

Provide more guidance for the documentation of the informed consent process in
section 12.3.

Clarify some inconsistencies and correct some minor errors and typos.
Changes to the protocol 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document showing deletions and insertions in comparison to the previous 
protocol version.  
Amended protocol sections 
The sections of the protocol affected by this global amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis:  
Section 1.4 
Summary of known and potential risks and benefits 
Section 3.1 
Study design 
Section 3.1.1.1 
Screening period 
Section 3.1.2  
Study duration 


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Section 4.3 
 
Inclusion criteria 
Section 4.4 
 
Exclusion criteria 
Section 4.5.2  
Acceptable methods of contraception 
Section 5.1.10  
Premature discontinuation of study treatment 
Section 5.1.11.2 
Renal failure 
Section 5.2.2  
Mandatory concomitant therapy 
Section 5.2.3  
Allowed concomitant therapy 
Section 7.1.1.2 
Re-screening 
Section 7.2.1.1 
Hypertension history 
Section 7.2.3.3 
Weight and height 
Section 7.2.5  
Biomarker assessments 
Section 9.5 
 
Reporting of study treatment overdose, misuse, and abuse 
Section 11.3  
Database management 
Section 12.3  
Informed consent 
Section 13 
 
References 
Section 14 
 
Appendices 
Summary of previous amendments 
Amendment Date 
Main reason(s) 
1 
19 September 2018  Merge 
components 
of 
several 
local 
amendments which were issued to address the 
feedback from health authorities to the global 
protocol ID-080A301 Version 1 to keep 
consistency in the performance of the study 
across all countries.  

Modify the exclusion criteria 5, 16 and 18.

Removed 
the 
NT-proBNP 
criterion 
at
randomization.


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PROTOCOL SYNOPSIS ID-080A301 
TITLE 
Multi-center, blinded, randomized, PaRallEl-group, Phase 3 study 
with aproCItentan in Subjects with ResIstant HypertensiON 
ACRONYM 
PRECISION 
OBJECTIVES 
The primary objective of the study is to demonstrate the blood 
pressure (BP) lowering effect of aprocitentan when added to 
standard-of-care in true resistant hypertension (RHT) subjects. 
The secondary objectives of the study are: 

to demonstrate that the effect of aprocitentan on BP is durable
when added to standard-of-care in true RHT subjects,

to evaluate the long-term safety and tolerability of aprocitentan
in true RHT subjects during 48 weeks of treatment.
DESIGN 
The study consists of four periods: a screening period, a placebo 
run-in (RI) period, a randomized treatment period and a safety 
follow-up (FU) period. 
Screening period 
This period lasts between 4 and 12 weeks. The purpose of the 
screening period is to select RHT subjects and confirm the diagnosis 
of true RHT. 
During this period the background antihypertensive medication 
(except beta-blockers) of subjects will be standardized by switching 
to a fixed combination of a calcium channel blocker (CCB), an 
angiotensin receptor blocker (ARB) and a diuretic.  
Placebo RI period 
This single-blind (SB) period lasts for 4 weeks during which 
placebo will be added to the standardized background 
antihypertensive therapy in all subjects. The purpose of this period 
is to confirm that BP remains uncontrolled despite administration of 
placebo for 4 weeks. 
Randomized treatment period 
This period lasts for 48 weeks. The purpose of this period is to 
evaluate the primary and secondary objectives of the study. 


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This period consists of 3 sequential parts: 

In the first double-blind (DB) part of 4 weeks subjects will be
randomized to aprocitentan 25 mg, aprocitentan 12.5 mg or
placebo in a 1:1:1 ratio;

In the second SB part of 32 weeks all subjects will receive
aprocitentan 25 mg;

In the third DB withdrawal (WD) part of 12 weeks subjects
will be re-randomized to aprocitentan 25 mg or placebo in a
1:1 ratio.
The End-of-Treatment (EOT) visit will take place at Week 48 
(i.e., end of DB-WD part) or earlier in the event of premature 
discontinuation of study treatment. The EOT visit should preferably 
take place on the day of the last dose of study treatment but, in any 
case, no later than 7 days after the last dose of study treatment. 
Follow-up (FU) Period 
The safety FU period starts on the day after the last dose of study 
treatment and ends at least 30 days thereafter. For subjects who 
discontinued during the RI period there will be a safety FU call. For 
randomized subjects, it will be a safety FU visit. 
The End-of-Study (EOS) is reached when the subject has completed 
the safety FU visit/call.  
NUMBER OF 
SUBJECTS 
Approximately 4000 subjects are expected to be screened, in order 
to enroll about 1500 subjects with diagnosis of RHT into the SB 
placebo RI period and to randomize 600 subjects. A total of 
560 subjects are expected to complete the DB treatment part 
(Week 4) and at least 380 subjects should enter the DB-WD part 
(Week 36). It is expected that at least 300 subjects will complete the 
DB-WD part (Week 48).  
PLANNED 
DURATION 
Approximately 45 months from First Subject First Visit 
(i.e., screening visit of first subject) to Last Subject Last Visit 
(i.e., safety FU visit of last subject). 


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SITE(S) 
/ COUNTRY(IES) 
Approximately 200 sites in approximately 25 countries in Asia, 
Australia, Europe, and North America (planned). 
INCLUSION 
CRITERIA 
The complete list of inclusion criteria is provided in the core text. 
The main criteria per study period are: 
Screening criteria 
This study will enroll adult male and female subjects > 18 years old 
with RHT defined as: 
Mean sitting systolic BP (SiSBP) ≥ 140 mmHg measured by 
unattended automated office blood pressure measurement 
(AOBPM) despite a background antihypertensive medication of at 
least 3 different pharmacological classes for at least 4 weeks before 
the screening visit (Visit 1).  
RI entry criteria 
Subjects with a confirmed diagnosis of RHT who are on 
standardized background antihypertensive therapy for at least 
4 weeks will enter the placebo RI period if their mean trough SiSBP 
is ≥ 140 mmHg as measured by AOBPM. 
Randomization criteria 
Subjects who completed the RI period and who have a mean trough 
SiSBP ≥ 140 mmHg as measured by AOBPM will be randomized. 
EXCLUSION 
CRITERIA 
The complete list of exclusion criteria is provided in the core text. 
The main exclusion criteria are: 

Apparent/pseudo RHT due to white coat effect, medical
inertia, poor therapeutic adherence, or secondary causes of
hypertension (except sleep apnea)

Confirmed 
severe 
hypertension 
(grade 
3): 
mean
SiSBP ≥ 180 mmHg and/or sitting diastolic blood pressure
(SiDBP) ≥ 110 mmHg, measured by AOBPM at two different
time points.
STUDY 
TREATMENTS 
Placebo tablets will be administered during the RI period. 


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Investigational treatment 
During the DB part, aprocitentan 12.5 and 25 mg tablets will be 
administered. 
During the SB part, aprocitentan 25 mg tablets will be administered. 
During the DB-WD part, aprocitentan 25 mg tablets will be 
administered.  
Comparator 
Placebo tablets will be administered during the DB and DB-WD 
parts of the study.  
Placebo tablets, aprocitentan 12.5 mg tablets and aprocitentan 
25 mg tablets will be indistinguishable. 
CONCOMITANT 
THERAPY 
Mandatory therapy 
Background antihypertensive medication will be standardized to a 
fixed combination of a CCB (amlodipine), an ARB (valsartan) and 
a diuretic (hydrochlorothiazide, HCTZ). 
The standardized background antihypertensive therapy will be 
initiated during the screening period, at the latest 4 weeks before the 
start of the RI period, and will be continued until EOS. 
Two dose strengths of amlodipine, 5 and 10 mg, will be available in 
the 
fixed 
combination. 
The 
standardized 
background 
antihypertensive therapy will be 10/160/25 or 5/160/25 mg of 
amlodipine/valsartan/HCTZ, respectively. The selection of the 
amlodipine dose strength for an individual subject (either 5 or 
10 mg) is at the investigator’s discretion and may vary during the 
screening period. It is required to use the maximal tolerated dose of 
the background antihypertensive therapy (i.e., 10 mg amlodipine, if 
there is no tolerability issue) from start of the RI period. The dose 
strength must be kept stable for at least 1 week before Day –1 (end 
of the RI period) until the end of the DB part (i.e., Week 4) and 
during the DB-WD part. The dose strength might be adjusted later 
on, during the SB aprocitentan part.  


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Allowed concomitant therapy 
Treatments considered necessary for the subject’s wellbeing and not 
categorized as forbidden concomitant medications are allowed 
during the study.  
In particular, the following therapies are allowed with the provision 
that they have been initiated at least 4 weeks prior to the screening 
visit and that the dose is kept stable until the EOT: 

Beta blockers;

Alfuzosin and tamsulosin (alpha-adrenergic receptors blockers)
for prostatic symptoms;

Hormonal contraceptives;

Estrogen-replacement treatment;

Sodium-glucose co-transporter 2 inhibitors;

Low dose acetylsalicylic acid for cardiovascular prevention;

Erythropoiesis-stimulating agents;

Psychiatric drugs.
In addition, the following therapies are allowed with the provision 
that they have been initiated at least 4 weeks prior to the screening 
visit and that the dose is kept stable until the end of the DB part 
(i.e., Week 4):  

Non-steroidal anti-inflammatory drugs;

Selective serotonin reuptake inhibitors and anxiolytics (such as
benzodiazepine).
During the SB aprocitentan part and DB-WD part, if, in the 
investigator’s opinion, the BP of a subject is not sufficiently 
controlled, antihypertensive rescue medication can be added as 
described in Section 5.2.3.1. 
After Randomization, the dose of the existing diuretic (HCTZ) can 
be increased or a new diuretic can be added in the event of fluid 
retention as judged by the investigator as described in 
Section 5.2.3.2. 
Forbidden concomitant therapy 
From the screening visit until the EOT visit any drug which may 
affect BP (other than those mentioned above) is forbidden. A list of 
medications is provided in Appendix 1. 


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ENDPOINTS 
Primary efficacy endpoint 
The primary efficacy endpoint is the change from baseline to 
Week 4 of DB treatment in mean trough SiSBP measured by 
AOBPM. 
Secondary efficacy endpoints 
The key secondary endpoint is the change from Week 36 (i.e., start 
of DB-WD) to Week 40 in mean trough SiSBP measured by 
AOBPM.  
The other secondary efficacy endpoints are: 

Change from baseline to Week 4 of DB treatment in mean
trough SiDBP measured by AOBPM;

Changes from baseline to Week 4 of DB treatment in 24 h mean
systolic BP (SBP) and diastolic BP (DBP) measured by
ambulatory blood pressure monitoring (ABPM);

Change from Week 36 to Week 40 of DB-WD treatment in mean
trough SiDBP measured by AOBPM;

Changes from Week 36 to Week 40 of DB-WD treatment in 24 h
mean SBP and DBP measured by ABPM.
Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Main safety endpoints 

Treatment-emergent1 adverse events (AEs);

Treatment-emergent1 serious AEs;

Treatment-emergent1 AEs leading to premature discontinuation
of study treatment;

Treatment-emergent1 major adverse cardiac events (MACE),
defined as cardiovascular death, non-fatal myocardial infarction
(MI), and non-fatal stroke; only those events confirmed by
Central Adjudication Committee (CAC) will be considered;

Treatment-emergent1 MACE-plus, defined as cardiovascular
death, non-fatal MI, non-fatal stroke and hospitalization for
heart failure; only those events confirmed by CAC will be
considered;

Increase of the dose of an existing diuretic or addition of a new
diuretic due to fluid retention;


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1Any AEs/abnormalities temporally associated with the use of study 
treatment (from RI placebo initiation until 30 days after study 
treatment discontinuation) whether or not considered by the 
investigator as related to study treatment. 
Pharmacokinetic endpoints 

Trough plasma concentration of aprocitentan at Week 4 of the
DB part.
ASSESSMENTS 
Refer to the schedule of assessments in Table 2 and Table 3. 
STATISTICAL 
METHODOLOGY 
Analysis sets 
The Full Analysis Set (FAS) includes all subjects who were 
randomized and have a baseline SiSBP, measured by AOBPM. This 
data set will be used for the evaluation of the primary endpoint. 
The Per Protocol Set (PPS) includes all subjects from the FAS 
without a major protocol deviation (to be defined in the Statistical 
Analysis Plan).  
The modified FAS (mFAS) includes all subjects in the FAS who 
were re-randomized in the DB-WD part of the study and have a 
Week 36 SiSBP, measured by AOBPM. This data set will be used 
for the evaluation of the key secondary endpoint. 
The ABPM FAS (aFAS) includes all subjects from the FAS who 
have a baseline 24 h mean SBP, measured by ABPM. 
The modified aFAS (maFAS) includes all subjects from the aFAS 
who were re-randomized in the DB-WD part of the study and have 
a Week 36 24 h mean SBP, measured by ABPM. 
The Safety Analysis Set (SAF) includes all randomized subjects 
who received at least one dose of study treatment in the DB part. 
The modified SAF (mSAF) includes subjects from the SAF who 
received at least one dose of study treatment in the DB-WD part. 
Statistical hypotheses 
Three null hypotheses will be tested in this study. The first two 
hypotheses (H10 and H20) will be tested in parallel using the 
Bonferroni correction. The third hypothesis (H30) will only be tested 
if H10 or H20 is rejected. 
The first null hypothesis H10 is that there is no difference between 
aprocitentan 25 mg and placebo in the DB part in the mean change 


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from baseline to Week 4 in mean trough SiSBP. This hypothesis 
will be tested at a two-sided significance level of 0.025. 
The second null hypothesis H20 is that there is no difference between 
aprocitentan 12.5 mg and placebo in the DB part in the mean change 
from baseline to Week 4 in mean trough SiSBP. This hypothesis 
will be tested at a two-sided significance level of 0.025. 
The third null hypothesis H30 is that there is no difference between 
aprocitentan 25 mg and placebo in the DB-WD part in the mean 
change from Week 36 to Week 40 in mean trough SiSBP. This 
hypothesis will only be tested if H10 or H20 has been rejected: at a 
two-sided significance level of 0.05 if both H10 and H20 have been 
rejected and at a two-sided significance level of 0.025 if only one of 
the H10 and H20 has been rejected. This way the overall type I error 
is protected at 0.05. 
Type I error and power 
The power is set to 90% for the third null hypothesis (H30) which 
(under the assumptions made in the sample size calculations) 
implies > 90% power for the first and second null hypothesis. 
Analysis of the primary efficacy variable 
The main analysis for the DB part will be conducted on the FAS. 
AOBPM measurements obtained after premature discontinuation of 
DB treatment will be excluded from this analysis (i.e., considered 
as missing). 
Changes from baseline to post-baseline visits up to Week 4 in mean 
trough SiSBP will be analyzed using a mixed model with factors for 
treatment group, time, and treatment by time interaction and 
covariates for baseline SiSBP and the interaction between baseline 
and time. An unstructured covariance matrix will be used to account 
for the correlation between repeated measurements from the same 
subject. 
Least Squares Mean (LSM) differences vs placebo at Week 4 and 
their 97.5% confidence intervals (CIs) will be obtained from the 
model. The associated P-values will be used to test the first and 
second null hypotheses.  


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Based on the Phase 2 study, AC-080A201, it is expected that 5% of 
subjects will have a missing Week 4 AOBPM. Missing data will not 
be imputed but will be handled by the mixed model assuming that 
the data are missing at random (MAR). The impact of deviations 
from the MAR assumption will be investigated in sensitivity 
analyses using control-based multiple imputation assuming the data 
in the aprocitentan groups are missing not at random.  
Analysis of the key secondary efficacy variable 
The main analysis for the DB-WD part will be conducted on the 
mFAS. 
AOBPM 
measurements 
obtained 
after 
premature 
discontinuation 
of 
DB-WD 
treatment 
or 
initiation 
of 
antihypertensive rescue medication in the DB-WD part will be 
excluded from this analysis (i.e., considered as missing). 
Changes from Week 36 to visits up to Week 48 in mean trough 
SiSBP will be analyzed using a mixed model with factors for 
stratum (in the re-randomization), treatment group, time, and 
treatment by time interaction, covariates for Week 36 SiSBP and the 
interaction between Week 36 and time and an unstructured 
covariance matrix. 
LSM differences vs placebo for the change from Week 36 to 
Week 40 and their 95% CIs will be obtained from the model. The 
associated P-values will be used to test the third null hypothesis. 
It is expected that 10% of subjects in the mFAS will have a missing 
Week 40 AOBPM. The missing data handling and sensitivity 
analyses will be similar to those described for the analysis of the 
primary efficacy endpoint. 
Analysis of the other secondary efficacy variables 
The other secondary efficacy variables will be analyzed at α=0.05 
(two-sided) using 95% CIs. 

Change from baseline to Week 4 of DB treatment in mean
trough SiDBP measured by AOBPM will be analyzed in the
FAS using the same model as specified for SiSBP in the DB
part.

Changes from baseline to Week 4 of DB treatment in 24 h
mean SBP and DBP measured by ABPM will be analyzed in
the aFAS using an Analysis of Covariance (ANCOVA) with a


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factor for treatment group and a covariate for baseline 24 h 
mean SBP (or DBP).  

Change from Week 36 to Week 40 of DB-WD treatment in
mean trough SiDBP measured by AOBPM will be analyzed in
the mFAS using the same model as specified for SiSBP in the
DB-WD part.

Changes from Week 36 to Week 40 of DB-WD treatment in
24 h mean SBP and DBP measured by ABPM will be analyzed
in the maFAS using the same ANCOVA as described for
changes from baseline to Week 4 of DB treatment.
Safety analyses 
Safety analyses in the DB and SB aprocitentan parts will be 
performed on the SAF. Safety analyses in the DB-WD part will be 
performed on the mSAF. 
Safety endpoints will be summarized by study part (DB, SB and 
DB-WD; DB+SB combined where appropriate) and treatment 
group 
(within 
study 
part) 
using 
descriptive 
statistics 
(e.g., percentages of subjects). 
Specific safety endpoints will be analyzed using time-to-event 
methods (Kaplan-Meier plot, Cox model), with time starting at 
Randomization and accounting for treatment switching (as part of 
the study design). 
Interim analysis 
No interim analysis is planned. 
Sample Size 
The sample size is driven by the power for the key secondary 
endpoint. The within-group standard deviation for the change from 
Week 36 to Week 40 in mean trough SiSBP (measured by AOBPM) 
is expected to be around 15 mmHg based on study AC-080A201. A 
difference vs placebo (‘delta’) of at least 5 mmHg in the DB-WD 
part is considered clinically relevant.  
With a type I error of 0.05 (two-sided; if both H10 and H20 have been 
rejected), the size of the mFAS needed for 90% power to detect a 
difference of 5 mmHg between aprocitentan 25 mg and placebo 


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would be 380 subjects (190 in each of the two groups in the DB-WD 
part).  
In order to have 380 subjects in the DB-WD part, a total of 
600 subjects will be randomized (200 in each of the three groups in 
the DB part of the study).  
For the change from baseline to Week 4 in mean trough SiSBP 
measured by AOBPM (primary endpoint), the clinically relevant 
difference vs placebo is around 6 mmHg. The power to detect this 
difference is well over 90%: 
Delta (mmHg) 
5.5 
6.0 
6.5 
Power* 
92% 
96% 
98% 
*alpha=0.025 two-sided
In case only one of the two doses in the DB part is statistically 
significantly better than placebo on the primary endpoint, the 
secondary endpoint must be tested at alpha=0.025 (two-sided). In 
that case the power for the DB-WD part is 84%. On average 
(assuming that testing at 0.025 is less likely than at 0.05), the power 
for the DB-WD part is approximately 88%. 
If the drop-out rate is greater than anticipated the sample size may 
be increased in order to ensure sufficient power for the DB-WD part. 
The sample size will not be decreased below 600. 
STUDY 
COMMITTEES 
An independent CAC will review and confirm all reported cases of 
MACE and MACE-plus in a blinded fashion. The composition and 
operation of the CAC is described in the CAC charter. 
An Independent Data Monitoring Committee (IDMC) has the 
overall responsibility for safeguarding the interests of subjects by 
monitoring the benefit-risk ratio and making appropriate 
recommendations based on all the reported data and thus ensuring 
that the study is being conducted with the highest scientific and 
ethical standards. The IDMC will be fully operational prior to 
enrollment of the first subject into the study. The composition and 
operation of the IDMC is described in the IDMC charter. 


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PROTOCOL 
1 
BACKGROUND 
1.1 Hypertension and resistant hypertension 
Hypertension (i.e., elevated blood pressure [BP]) is a “silent” killer that rarely causes 
symptoms. Hypertension is defined in adults by (office) systolic/diastolic BP (SBP/DBP) 
≥ 140/90 mmHg and is sub-classified into grade 1 (mild): 140/90 ≤ BP < 160/100, grade 2 
(moderate): 160/100 ≤ BP < 180/110, or grade 3 (severe): BP ≥ 180/110 [Williams 2018, 
Chobanian 2003]. This condition represents a significant global public health concern, as 
it contributes to vascular and renal morbidity, cardiovascular mortality, and economic 
burden [Lim 2012, Go 2013].  
Despite current knowledge on the management of hypertension and the availability of 
numerous effective antihypertensive drugs, hypertension remains inadequately controlled 
in many patients. A number of these uncontrolled patients are considered to have so-called 
“resistant hypertension” (RHT) or “difficult-to-control hypertension”, which is defined as 
uncontrolled BP (i.e., failure to lower BP to a pre-defined threshold) in patients adhering 
to lifestyle modifications and to an appropriate regimen of three or more antihypertensive 
drugs from different pharmacological classes, including a diuretic, in the absence of 
secondary cause of hypertension [Calhoun 2008, Williams 2018].  
“True” RHT should not be confused with “pseudo” or “apparent” RHT, which is far more 
common than true RHT. White coat effect, improper BP measurement, poor patient 
adherence, drug-related hypertension, and physician’s clinical inertia (i.e., inadequate dose 
of antihypertensive medications or inappropriate combinations) are frequent causes of 
pseudo RHT and need to be ruled out before the diagnosis of true RHT is made 
[White 2014, Sheppard 2017]. Secondary causes of hypertension (e.g., renovascular 
disease, hyperaldosteronism due to aldosterone-producing adenoma, pheochromocytoma, 
and thyroid disease) can also cause apparent RHT and require specific targeted therapy. 
Diagnosis of true RHT requires exclusion of these various medical situations according to 
local medical practice. 
The estimated prevalence of RHT varies from 2 to 30% of the hypertensive population 
[Sheppard 2017, Williams 2012]. This broad range of the estimate is mainly due to the 
different sources of information (e.g., insurance healthcare systems, registries, 
well-controlled therapeutic clinical trials). It is not always clear from these reports whether 
the prevalence is for “apparent” or “true” RHT.  
A critical characteristic of most “true” RHT patients is their complex medical condition. 
Compared to the hypertensive population, RHT patients are more likely to be older 
(> 75 years), to be of black race, to have a higher body mass index, albuminuria, reduced 
renal function, self-reported co-morbidities of diabetes mellitus (DM), coronary heart 


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disease, and sleep apnea [Myat 2012, White 2014]. Chronic kidney disease (CKD) and 
DM, in particular, amplify the RHT patients’ vulnerability and increase the complexity of 
RHT treatment [De Nicola 2013, Solini 2014, Rossignol 2015]. In addition, in RHT 
patients, the risk of cardiovascular events is much higher than in the rest of the hypertensive 
population. This has been consistently shown in different settings (i.e., clinical trials, 
observational studies, and international registries) comparing RHT vs non-RHT patients 
[Daugherty 2012, Kumbhani 2013, Bangalore 2014, Tsioufis 2014]. Consequently, it is 
important to control BP in the RHT population. 
1.1.1 Current treatment of RHT 
The RHT population is, by definition, on a background therapy of three or more 
antihypertensive medications at maximal tolerated doses, which, according to most clinical 
guidelines, include: an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin 
receptor blocker (ARB), a long-acting thiazide diuretic and a calcium channel blocker 
(CCB), which is the most commonly used type of third background agent in RHT 
[Poulter 2015]. For some patients, individualization of therapy is needed; e.g., for patients 
with ischemic heart disease, a beta-blocker is often used in addition to the aforementioned 
medications.  
The choice of the fourth-line therapy prescribed to control BP in RHT patients has not been 
unequivocally determined. The first therapeutic option recommended by European Society 
of Cardiology (ESH) / European Society of Cardiology (ESC) guidelines [Williams 2018] 
is to reinforce the diuretic therapy, by adding one or more diuretic agents with different 
mechanisms of action to the diuretic already used in the background therapy. 
Potassium-sparing diuretics, such as a mineralocorticoid receptor antagonists (MRAs), are 
recommended. The most commonly used MRA in RHT is spironolactone. The effect of 
this drug as a fourth-line antihypertensive medication in RHT has been brought to the 
forefront by the positive results of the crossover study PATHWAY-2. This study showed 
a larger BP decreasing effect of spironolactone (25 mg increased to 50 mg after 6 to 
12 weeks) compared to bisoprolol (beta-blocker), and doxazosin (alpha-1 antagonist), in 
RHT patients [Williams 2015]. However, the insufficient representation of patients with 
CKD stage 3 which is most frequent comorbidities associated with RHT challenges the 
external validity of this study [Rossignol 2015]. The use of spironolactone in combination 
with renin angiotensin system (RAS) blocking medication might potentially increase the 
risk of hyperkalemia in RHT patients as reported in heart failure [Juurlink 2004] and 
consequently, might limit the safe use of spironolactone in these patients [Krogager 2017]. 
Other available antihypertensive therapeutic classes not used in the already prescribed 
background therapies can also be proposed as fourth-line therapies in RHT patients 
(e.g., alpha-1 antagonists, centrally active alpha-2 agonists, direct vasodilators). These 


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therapies have well-known limitations, especially due to their adverse effects, which often 
lead to discontinuation of therapy [Lancet 1981, Thomopoulos 2016a].  
An alternative therapeutic approach in the management of RHT is catheter-based renal 
denervation. However, there are several limitations in its development program such as 
small sample sizes, lack of sham-control groups, suboptimal background or comparative 
antihypertensive therapies, lack of strict ambulatory blood pressure monitoring (ABPM) 
assessment, and requirement of specialized expertise by the involved radiologists. Due to 
these limitations, a definitive conclusion cannot be drawn on its efficacy and applicability 
in RHT [Cai 2017].  
1.1.2 Unmet medical need in RHT 
As outlined above, even with the current knowledge on the management of hypertension 
and availability of numerous antihypertensive therapies, hypertension and particularly 
RHT remains a global public health concern, because: 
 
Uncontrolled BP despite treatment with 3 or more antihypertensive medications 
triggers deleterious cardiovascular outcomes; 
 
Comorbidities such as CKD and DM associated with RHT trigger poor prognosis and 
induce therapeutic challenges; 
 
RHT patients are polymedicated; any new therapy proposed in fourth line must be safe 
on top of existing mandatory background therapies; 
 
All current therapies that can be proposed as fourth-line therapies in RHT present 
limitations due to adverse effects, triggering discontinuation and amplifying the 
well-known poor adherence in this population. 
There is a medical need for additional pharmacological therapy acting on pathway(s) 
different from those currently used [Dhaun 2008, Oparil 2015] in line with the 
pathophysiology of RHT [see Section 1.2.1].  
1.2 Aprocitentan 
1.2.1 Mechanism of action and rationale for development in RHT 
Aprocitentan is an orally active dual endothelin (ET) receptor antagonist (ERA), selected 
for clinical development for the treatment of RHT. The peptide ET-1 is a potent 
vasoconstrictor that can also cause neurohormonal activation, increased aldosterone 
synthesis and secretion, induce vascular hypertrophy and remodeling, and endothelial 
dysfunction. ET-1 and its two receptors, ETA and ETB, mediate biological processes that 
may contribute to the pathogenesis of hypertension. 
RHT had been frequently associated with volume expansion [Gaddam 2008, 
Aprocitentan IB], which is a feature of salt-sensitive hypertension. Plasma ET-1 


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concentrations are increased in hypertensive African-Americans [Ergul 1996], a population 
with an increased prevalence of salt-sensitive, low-renin hypertension and also RHT 
[Chrysant 1979, Luft 1979]. ET-1 production is also increased in patients with risk factors 
to RHT such as obesity, DM, and CKD. RHT may therefore represent an “ET-dependent 
form” of hypertension. Accordingly, ERAs demonstrate greater efficacy in salt-dependent 
/ low renin than in high/normal renin animal models of hypertension [Schiffrin 1998]. 
Nonclinical data with aprocitentan have confirmed these expectations and findings 
[Aprocitentan IB]. 
The mechanism of action of aprocitentan seems appropriate to the RHT pathophysiological 
profile [Dhaun 2008] and is distinct from drugs interfering with the RAS or producing 
sodium depletion [Davenport 2016]. Therefore, it is anticipated that it can be combined 
with background therapy including RAS blockers and diuretics without increasing their 
risks while providing additional BP lowering potential [Weber 2009].  
1.2.2 Nonclinical summary 
Nonclinical studies have been conducted to characterize the pharmacology and 
pharmacokinetics (PK) of aprocitentan. In rat models of systemic hypertension, single and 
chronic oral administration of aprocitentan dose-dependently decreased mean arterial BP 
without increasing heart rate (HR) and showed synergistic BP-lowering effects in two 
different animal models (spontaneously hypertensive rats, deoxycorticosterone acetate-salt 
rat model) when combined with an ARB.  
More detailed information on the nonclinical data generated on aprocitentan can be found 
in the Investigator’s Brochure (IB) [Aprocitentan IB]. 
1.2.3 Clinical summary 
Phase 1 clinical studies 
A total of six Phase 1 studies have been clinically completed; these studies characterized 
the safety, tolerability, PK, and pharmacodynamics (PD) of aprocitentan in 144 male and 
female subjects. In these studies, aprocitentan was given as single doses of up to 600 mg 
and multiple doses up to 100 mg once daily.  
Pharmacokinetics 
After absorption of aprocitentan, with peak plasma concentrations reached at 3–9 h for the 
different doses, elimination was slow, with an apparent elimination half-life of 
approximately 44 h. The PK properties of aprocitentan after single and multiple dosing 
were similar and support once-daily dosing. Steady-state conditions were reached by Day 8 
of dosing with an accumulation of aprocitentan by approximately 3-fold. Based on PK, 
aprocitentan can be administered with or without food and no dose adjustment is required 


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for sex, elderly subjects, and subjects with mild, moderate, or severe (i.e., estimated 
glomerular filtration rate [eGFR] ≥15 mL/min) renal function impairment.  
A clinical drug-drug interaction (DDI) study with midazolam showed that aprocitentan did 
not influence the PK of drugs that are substrates of any cytochrome P450 and, therefore, 
these drugs can be administered concomitantly without need for dose adaptation. Likewise, 
a clinical DDI study with rosuvastatin showed that aprocitentan did not influence the PK 
of drugs that are substrates of the efflux transporter breast cancer resistance protein, 
therefore these drugs can be administered concomitantly without need for dose adaptation. 
The primary results of the human absorption, distribution, metabolism, elimination study 
showed that urine represented the most important elimination route of aprocitentan and its 
metabolites. Formation of the two most abundant metabolites of aprocitentan in urine and 
feces, respectively, is not expected to be dependent on cytochrome P450 (CYP)3A4. 
Therefore, aprocitentan can be concomitantly administered with drugs that are inhibitors 
or inducers of CYP3A4.  
More detailed information on nonclinical and clinical PK data generated on aprocitentan 
can be found in the IB [Aprocitentan IB]. 
Pharmacodynamics 
PD were investigated in the mechanistic Phase 1 study AC-080-102 in which healthy male 
subjects received a twice daily (o.d.) dose of aprocitentan (10, 25 or 50 mg) or placebo for 
9 days in a 2-way cross-over design [D-18.046]. An extra sodium load was given from 
Day 3 to Day 9 to ensure that subjects had a sodium excretion > 170 mmol/day. PK and 
PD variables were assessed on Day 1 and Day 9 with aprocitentan at steady-state 
conditions. 
The primary endpoint was the change from baseline (Day 1) to Day 9 in body weight (kg). 
A non-inferiority approach was applied in which at least one aprocitentan dose had to be 
non-inferior to placebo with respect to change from baseline to Day 9 in body weight, 
defined as the upper limit of the 90% confidence interval (CI) for the difference excluding 
1 kg.  
The 10 mg aprocitentan dose was considered non-inferior to placebo, despite a (statistically 
non-significant) mean increase in body weight of +0.425 kg since the upper limit of the 
90% CI did not exceed 1 kg. In contrast, for both the 25 and 50 mg doses, the upper limit 
of the 90% CI exceeded 1 kg, therefore, for both non-inferiority was not concluded. The 
mean body weight increases were +0.771 and +0.825 kg with 25 and 50 mg aprocitentan, 
respectively. The increases in body weight were considered to be modest, with a minimal 
difference between 25 and 50 mg aprocitentan, and were not associated with peripheral 
edema in these healthy subjects. In addition, decreases in hemoglobin vs placebo were 


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observed, for which exploratory modeling suggested a dose-relationship, together with 
slight, non-dose-dependent decreases in hematocrit. When plasma uric acid mean changes 
from baseline to Day 9 were corrected for placebo, a decrease was observed with the two 
higher doses of aprocitentan, but not at 10 mg. 
Aprocitentan did not affect sodium excretion in a clear way in the healthy salt-loaded 
subjects in this study, as was demonstrated by unchanged sodium clearance, fractional 
excretion of sodium, and sodium excretion rates between baseline and Day 9. Other 
exploratory renal function parameters assessed in this study did not identify clear signs of 
sodium retention, even though the observed increases in body weight suggested that some 
extent of sodium retention should have at least transiently been present. 
Plasma hormones were measured in study AC-080-102 to assess any possible development 
of adaptive mechanisms. Due to the high salt intake, plasma aldosterone and renin activity 
levels were low, and there were no clear patterns of changes in body fluid regulating 
hormones between baseline and Day 9. 
Tolerability and safety 
In the entry-into-human study AC-080-101, aprocitentan was well tolerated at single oral 
doses of up to and including 600 mg, and multiple oral doses of up to and including 100 mg 
o.d. for 10 days. No deaths or serious adverse events (SAEs) were reported.
After single-dose administration, under fasted conditions, more subjects reported adverse 
events (AEs) with increasing dose. The most frequently reported AEs were headache 
(10/30 subjects on aprocitentan 2/8 subjects on placebo with headache reported by all 
subjects treated with 600 mg aprocitentan), nausea (3 and 1, respectively), postural 
orthostatic tachycardia (3 and 1, respectively), and nasal congestion (2 and 1, respectively). 
There were no relevant differences in safety findings between subjects in fed and fasted 
conditions.  
After multiple-dose administration, whilst at lower doses there were no apparent 
differences in proportion of subjects reporting AEs compared with placebo (ranging from 
57–67% of the subjects on aprocitentan compared to 67% of the subjects on placebo). A 
larger proportion of healthy subjects (71%) and elderly subjects (83%) treated with 
100 mg/day aprocitentan reported AEs when compared to its matching placebo (67% and 
50%, respectively). The most frequently reported AE was headache. Reporting of headache 
increased with dose and was not observed in subjects treated with placebo.  
Compared with placebo and lower doses of aprocitentan, 100 mg aprocitentan appeared to 
increase body weight in both healthy adult and healthy elderly subjects. 


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The safety profiles of subsequent Phase 1 studies were in line with observations in study 
AC-080-101. 
More detailed information on clinical safety data generated on aprocitentan can be found 
in the IB [Aprocitentan IB]. 
Phase 2 dose-finding study AC-080A201 
A Phase 2 placebo- and active-controlled, dose-finding study explored four doses of 
aprocitentan (5, 10, 25, and 50 mg o.d.) on sitting DBP (SiDBP) measured at trough by 
unattended automated office blood pressure measurement (AOBPM) in subjects with 
grade 1 or 2 essential hypertension with no background therapy. Additionally, sitting SBP 
(SiSBP) and 24 hour SBP/DBP measured by ABPM, as well as the safety and tolerability 
of the four aprocitentan doses were evaluated. The active reference was 20 mg lisinopril 
o.d. The study consisted of a single-blind (SB) placebo period of 4–6 weeks, followed by
a double-blind (DB) treatment period of 8 weeks. A withdrawal (WD) period of 2 weeks
with SB placebo started after the end of the DB treatment period. After the last dose of the
SB WD study treatment, there was a safety follow-up (FU) period of at least 2 weeks.
A total of 490 subjects were randomized to placebo, aprocitentan 5, 10, 25 or 50 mg, or 
20 mg lisinopril in a 1:1:1:1:1:1 ratio. Overall, the key demographic and clinical 
characteristics of the study population at baseline were representative of the general 
essential hypertension population and well-balanced across all groups. 
At baseline, the average SiSBP/SiDBP was 149.7/97.6 mmHg (Per Protocol Set [PPS]). 
The mean changes from baseline to Week 8 in SiSBP/SiDBP in the placebo and 
aprocitentan 5, 10, 25 and 50 mg groups were –7.7/–4.9, –10.3/–6.3, –15.0/–9.9, 
–18.5/–12.0, –15.1/–10.0 mmHg, respectively. In the lisinopril 20 mg group the mean
change from baseline in SiSBP/SiDBP was –12.8/–8.4.
The differences vs placebo for SiSBP/SiDBP were –2.45/–1.31, –7.05/–4.93, 
–9.90/–6.99, –7.58/–4.95 mmHg for aprocitentan 5, 10, 25 and 50 mg respectively.
The primary efficacy objective for this study was met in that a dose-response relationship 
was detected among the placebo and aprocitentan groups for the change from baseline to 
Week 8 in mean SiDBP (primary endpoint; P < 0.0001). A quadratic model fitted the data 
best. A similar dose-response relationship was detected for the change from baseline to 
Week 8 in mean SiSBP (secondary endpoint). The results of the analyses for the ABPM 
endpoints were consistent with those for the primary endpoint.  
As observed with other ERAs, a dose-dependent decrease in hemoglobin (as well as 
hematocrit, protein and albumin) was observed at Week 8 in the aprocitentan groups, as 
compared to placebo and lisinopril 20 mg groups. Additionally, a dose-dependent increase 


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in estimated plasma volume (calculated based on changes in hemoglobin and hematocrit 
[Strauss 1951]) was detected ranging from 3.0% to 9.5% in the aprocitentan groups vs 
1.6% in the lisinopril 20 mg group and –0.3% in the placebo group. No change of weight 
was observed across all doses of aprocitentan. 
All four doses of aprocitentan were well tolerated. The proportions of subjects in the 
aprocitentan dose groups who had at least one AE during the DB study treatment period 
ranged from 22.0% to 40.2% and showed no apparent dose response. The incidences in the 
placebo (36.6%) and lisinopril (32.1%) groups were within the same range. The most 
frequently reported AEs in the 6 treatment groups were: headache, nasopharyngitis, upper 
respiratory tract infection, arthralgia, dizziness and pain in extremity. Edema AEs were 
reported for 4 subjects, 2 subjects each in the aprocitentan 25 mg (2.4%) and 50 mg (2.5%) 
groups.  
More detailed information can be found in the IB [Aprocitentan IB]. 
1.2.4 Aprocitentan dose rationale 
The doses of aprocitentan for clinical development in RHT were identified based on the 
results of the Phase 2 dose-finding study (AC-080A201) and were supported by the results 
of the AC-080-102 study in healthy subjects on a high sodium diet.  
In the Phase 2 dose-finding study placebo-corrected differences in the change from 
baseline to Week 8 in mean SiSBP/SiDBP were statistically significant for aprocitentan 
10 mg (P < 0.05 / P < 0.01), aprocitentan 25 mg (P < 0.001/ P < 0.0001) and aprocitentan 
50 mg (P < 0.01/ P < 0.01). Numerically, the 25 mg dose was the best dose 
(–9.90/–6.99 mmHg). The 10 mg (–7.05/–4.93 mmHg) and 50 mg (–7.58/–4.95 mmHg) 
doses were similar, indicating that a “plateau” of the dose response curve may have been 
reached.  
In the Phase 1 study AC-080-102, [Section 1.2.3] non-inferiority vs placebo in change from 
baseline to Day 9 in body weight could not be demonstrated for the doses of 25 and 50 mg 
aprocitentan. However, the increases in body weight were considered to be modest and 
were not associated with peripheral edema in these healthy subjects. Aprocitentan did not 
affect sodium excretion in a clear way in the healthy salt-loaded subjects and there were 
no clear signs of sodium retention. Statistical comparison of body weight changes from 
baseline of treatment vs placebo showed only a significant p-value of 0.017 for the 50 mg 
dose, suggesting that 25 mg could have a more favorable profile than 50 mg.  
In summary, aprocitentan in the range of 10 to 25 mg provides the best benefit (reduction 
of BP) / risk (hemoglobin decrease, weight increase) profile. Therefore, aprocitentan doses 
of 12.5 mg o.d. and 25 mg o.d. have been selected for further development. 


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1.3 Rationale of the study 
The rationale for this Phase 3 study is based on (i) the mechanism of action of aprocitentan 
that addresses the RHT pathophysiological mechanism [Dhaun 2008 and Section 1.2.1], 
and (ii) the recognition of an unmet medical need for these patients [see Section 1.1.2].  
1.4 Summary of known and potential risks and benefits 
Based on the mechanism of action of aprocitentan, current nonclinical data, and clinical 
data from the Phase 1 studies and Phase 2 study in adult subjects with essential 
hypertension on mono-therapy, it is anticipated that aprocitentan will reduce the BP of 
subjects participating in this study in a durable and safe manner. 
During the study subjects will be carefully followed at regular visits for up to 68 weeks in 
hypertension specialized centers. All visit assessments (e.g., BP measurement, blood 
sampling, electrocardiogram [ECG]) are part of the routine standard-of-care for subjects 
with RHT, although their frequency may be higher in the study. The most invasive 
procedure repeated at each visit will be blood sampling, which requires the use of needles. 
All subjects will be treated with aprocitentan 25 mg for 32 weeks in the SB aprocitentan 
part. In addition, an antihypertensive triple fixed combination will be provided to all 
subjects at least 4 weeks before entering the run-in (RI) period until the End-of-Study 
(EOS; i.e., for at least 60 weeks) to standardize their background antihypertensive 
medication. This fixed combination medication has been approved and commercialized for 
several years in different countries for treatment of hypertension. For detailed information 
refer to the package insert provided in the site file. 
The potential risks for subjects participating in this study are related to those based on the 
pre-clinical and clinical findings of aprocitentan [see Sections 1.2.2 and 1.2.3, and 
section 1.5 of the Aprocitentan IB].  
There is a potential risk in both placebo and aprocitentan treatment groups that BP may not 
be reduced. However, the placebo periods are limited to short periods of time [see 
Section 3.1.1.2 and 3.1.1.3]. It should be noted that no harm was reported when placebo 
was used for a similarly short period of time [see Section 3.2]. In addition, based on the 
Phase 2 data it is anticipated that aprocitentan will decrease BP. 
The following measures will contribute to minimize the risks for the subjects participating 
in the study: 

Exclusion of subjects with confirmed severe hypertension (i.e., grade 3), recent severe
cardiovascular disease (heart failure New York Heart Association [NYHA] stage III
and IV), N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 500 pg/mL, stroke,


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severe CKD (i.e., grade 5), low hemoglobin, and high alanine and aspartate 
aminotransferase (ALT/AST) [see Section 4.4].  

Use of a highly effective method of contraception for women of childbearing potential.

Laboratory tests performed prior to initiation of study treatment and frequently
thereafter [as defined in Table 2 and Table 3] until EOS.

Close follow-up of the subjects throughout the study with site visits see Section 7.1.

Possibility to add antihypertensive rescue medication at the discretion of the
investigator during the SB aprocitentan and DB-WD parts of the study in the event
that BP is not satisfactorily controlled (confirmed by second measurement), despite
confirmed adherence to standardized background antihypertensive therapy [see
Section 5.2.3.1].

Study-specific criteria for interrupting or stopping study treatment [see
Section 5.1.11].

Monitoring of safety and efficacy data by an Independent Data Monitoring Committee
(IDMC) [see Section 3.3.2].
It is the investigator’s responsibility to monitor the risk-benefit ratio of study treatment 
administration, as well as the degree of distress caused by study procedures on an 
individual subject, and to discontinue study treatment or the study if, based on medical 
judgment, he/she believes that continuation would be detrimental to the subjects’ 
well-being. 
For further information on the efficacy and safety profile of aprocitentan, please refer to 
the IB [Aprocitentan IB]. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to demonstrate the BP lowering effect of aprocitentan 
when added to standard-of-care in true RHT subjects. 
2.2 Secondary objectives 
The secondary objectives of the study are 

to demonstrate that the effect of aprocitentan on BP is durable when added to
standard-of-care in true RHT subjects

to evaluate the long-term safety and tolerability of aprocitentan in true RHT subjects
during 48 weeks of treatment.


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2.3
Other objectives

Evaluate steady-state trough plasma concentrations of aprocitentan after 4 weeks of
treatment.

Evaluate the ET system activity and the effect of aprocitentan on micro- and
macrovascular complications based on specific biomarkers.
3
OVERALL STUDY DESIGN AND PLAN
3.1
Study design
This is a prospective, multicenter, randomized, parallel-group, blinded Phase 3 study with 
aprocitentan in subjects with true RHT. 
The overall study design is depicted in [Figure 1]. 
Figure 1
Study design
Approximately 4000 subjects are expected to be screened, in order to enroll about 
1500 subjects with diagnosis of RHT into the SB placebo RI period. At least 600 subjects 
will be randomized and at least 300 subjects are expected to complete the study (i.e., the 
30 day safety follow-up period). The study will be conducted in approximately 200 sites in 
approximately 25 countries.
Once the randomization target has been met, the sponsor might decide to close the 
recruitment. In such a case, study participants still in the screening period may not enter 
the run-in period and be randomized.
3.1.1
Study periods
The study comprises the following consecutive periods:


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3.1.1.1 Screening period 
This period lasts between 4 and 12 weeks. It starts at the screening visit with the signing 
of the informed consent form (ICF) and ends the day before the subject enters the RI period. 
The purpose of the screening period is to select RHT subjects and confirm the diagnosis of 
true RHT.  
At least 4 weeks before the start of the RI period, the background antihypertensive 
medication (except beta-blockers) of subjects with diagnosis of true RHT and having mean 
trough SiSBP ≥ 140 mmHg measured by AOBPM will be standardized by switching to a 
fixed combination of a CCB (amlodipine), an ARB (valsartan) and a diuretic 
(hydrochlorothiazide [HCTZ]).  
In case a beta-blocker is used as one of the background antihypertensive medications or for 
any other indication (e.g., heart failure, angina, post-myocardial infarction [MI], atrial 
fibrillation), this can be kept, with the provision that it has been initiated and the dose kept 
stable for at least 4 weeks prior to the screening visit and that the dose is kept stable until 
the End-of-Treatment (EOT). 
The number of site visits is flexible during this period and depends on tests/assessments 
needed to be performed.  
3.1.1.2 Placebo run-in period 
This SB period lasts for 4 weeks, beginning with the first dose of SB placebo and ending 
at Randomization (after completion of the 24 h ABPM recording on the last dose of SB 
placebo). It consists of 3 site visits: Visit 2 at the start of the RI (i.e., 4 weeks before 
Randomization), Visit 3 (i.e., 2 weeks before Randomization) and Visit 4 at the end of the 
RI (Day –1; i.e., 1 day before Randomization). 
The purpose of this period is to confirm that mean trough SiSBP measured by AOPBM 
remains ≥ 140 mmHg despite administration of placebo for 4 weeks on top of the 
standardized background antihypertensive therapy. The rationale for administering placebo 
during the RI is discussed in Section 3.2. 
3.1.1.3 Randomized treatment period 
This period lasts for 48 weeks. It starts at Randomization (i.e., Day 1 of the DB part) and 
ends at the EOT visit (i.e., at end of the DB-WD part). 
This period consists of 3 sequential parts: 
Part 1 is DB, randomized, parallel-group and placebo-controlled and lasts for 4 weeks. 
Subjects will receive aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio. 
It starts at Randomization (i.e., Day 1) with the first dose of DB study treatment and ends 


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after completion of the Week 4 24 h ABPM recording on the last dose of DB study 
treatment. It consists of 3 site visits: Visit 4 at Randomization (i.e., Day 1), Visit 5 at 
Week 2 and Visit 6 at Week 4 (i.e., end of the DB part). 
The purpose of this period is to demonstrate the BP lowering effect of aprocitentan in true 
RHT subjects (i.e., the primary objective of the study). 
Part 2 is SB and single-arm and lasts for 32 weeks. All subjects will receive aprocitentan 
25 mg. It starts with the first dose of the SB study treatment (after completion of the Week 4 
24 h ABPM) and ends after completion of the Week 36 24 h ABPM recording on the last 
dose of SB treatment. It consists of 5 site visits: Visit 7 at Week 6, Visit 8 at Week 12, 
Visit 9 at Week 20, Visit 10 at Week 28 and Visit 11 at Week 36 (i.e., end of the SB 
aprocitentan part). 
Part 3 is DB-WD, randomized, parallel-group and placebo-controlled and lasts for 
12 weeks. Subjects will be re-randomized to aprocitentan 25 mg or placebo in a 1:1 ratio. 
This part starts with the first dose of the DB-WD study treatment (after completion of the 
Week 36 24 h ABPM recording) and ends after completion of the Week 48 (i.e., DB-WD 
EOT) assessments. It consists of 4 visits: Visit 12 at Week 38, Visit 13 at Week 40, Visit 14 
at Week 44 and Visit 15 at Week 48 (i.e., EOT).  
The purpose of parts 2 and 3 is to demonstrate that the BP lowering effect of aprocitentan 
on BP is sustained over a period of 36 weeks in true RHT subjects (i.e., the key secondary 
objective). 
EOT is at Week 48 (i.e., end of DB-WD part) or earlier in the event of premature 
discontinuation of study treatment. The EOT visit should preferably take place as soon as 
possible after the last dose of study treatment but, in any case, no later than 7 days. 
Premature discontinuation of study treatment is described in Section 5.1.10. 
3.1.1.4 Safety follow-up (FU) period 
The safety FU period starts on the day after the last dose of study treatment and ends at 
Visit 16 with a safety FU visit/call: 
 
For subjects who entered the RI period, but who were not randomized (i.e., who 
received only SB placebo) it will be a safety FU call.  
 
For randomized subjects it will be a safety FU visit. 
The safety FU visit/call must take place 30 (+3) days after the last dose of study treatment. 
For an individual subject, EOS corresponds to the safety FU call or safety FU visit. 
The visit schedule and protocol-mandated procedures will be performed according to the 
tables of assessments [Table 2 and Table 3] and as described in Section 7. 


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3.1.2 Study duration 
Subject participation in the study will be up to 68 weeks. 
The study starts with the first subject first visit and ends with the last subject last visit. The 
study is expected to last approximately 45 months. 
3.2 Overall study design rationale 
This study is designed to show that aprocitentan reduces BP and that this effect is sustained 
(durable) in subjects with RHT.  
This study has a RI period of 4 weeks. During this period, placebo will be administered in 
order to exclude potential placebo responders and, thus, reduce the placebo effect in the 
DB part. An RI period of at least 2, sometimes as long as 4, weeks was used for the 
development of antihypertensive agents. A prolonged RI period of 4 weeks may be 
necessary to avoid bias due to the regression-toward-the-mean phenomenon. 
[EMA 2016a]. 
3.2.1 Rationale for DB part 
The 4 weeks DB part is designed to demonstrate the effect of 2 doses of aprocitentan 
(12.5 and 25 mg) on BP at Week 4, compared to placebo. The analysis after 4 weeks of 
treatment reduces the likelihood of missing data. In addition, in the dose-finding study 
AC-080A201, at least 80% of the expected BP reduction was already observed in the first 
4 weeks of treatment. Placebo is used as the control group due to high variability of BP, 
especially on top of background therapies in true RHT subjects.  
The use of placebo does not create an unethical situation due to the following reasons: 

Subjects are already on background antihypertensive medications and severe (grade 3)
hypertensive subjects will not be allowed to enter into this study.

Subjects are closely followed during these 4 weeks with visits at Week 2 and Week 4.

Study-specific discontinuation criteria have been set-up [see Section 5.1.11].

Subjects who experience (confirmed) essential hypertension grade 3 must permanently
stop the study treatment.

Use of placebo in numerous recent placebo- or sham-controlled studies in similar
population (i.e., RHT) on stable triple background antihypertensive medications didn’t
report safety concern [Václavík 2011, Williams 2015, Bhatt 2014].

No irreversible harm was reported during this short-term period (4–8 weeks) by an
FDA meta-analysis of 590 individual hypertension clinical trials involving
64,438 subjects randomized to experimental drug and 21,699 randomized to placebo
[DeFelice 2008].


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3.2.2 Rationale for SB aprocitentan part and DB-WD part 
These 2 parts are designed to demonstrate the long-term BP lowering effect of aprocitentan. 
In chronic diseases (e.g., heart failure) or special population (e.g., pediatric) placebo cannot 
be administered for a long period of time or not at all. For these cases, a randomized WD 
design is now standard when the objective is to demonstrate that the long-term effect on 
BP is sustained [O’Neill 2012]. In a randomized WD design, a long-term SB active 
treatment part is followed by a DB-WD part in which subjects are randomized to 
investigational drug or placebo.  
In this study, all subjects who enter into the SB aprocitentan part will be treated for 
32 weeks with aprocitentan 25 mg. This period is followed by DB-WD part where subjects 
will remain either on aprocitentan 25 mg or switch to placebo in a 1:1 ratio for 12 weeks. 
The BP will be analyzed at Week 4 of the DB-WD period (i.e., Week 40) key secondary 
endpoint). This duration is selected and justified based on the half-life of aprocitentan 
(i.e., 44 hours). The total duration of the DB-WD part will be 12 weeks to be able to also 
explore the durability at Week 8 and Week 12. 
3.3 Study committees 
3.3.1 Independent Central Adjudication Committee 
An independent Central Adjudication Committee (CAC) provides ongoing review of all 
reported cases of major adverse cardiac events (MACE) and MACE-plus in a blinded 
fashion. To ensure the proper and comprehensive review and adjudication of MACE 
events, additional subject data may be requested by the CAC. 
The composition and operation of the CAC is described in the CAC charter. 
3.3.2 Independent Data Monitoring Committee 
An IDMC has the overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study and making appropriate 
recommendations based on the reported data, thus ensuring that the study is being 
conducted to the highest scientific and ethical standards. The IDMC will be fully 
operational prior to enrollment of the first subject into the study. The composition and 
operation of the IDMC are described in the IDMC charter. 
Unblinded data will be delivered to the IDMC by an Independent Statistical Analysis 
Center (ISAC). 


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4 
STUDY POPULATION 
4.1 Selection of study population 
RHT is defined as BP that is not controlled to a pre-defined threshold [described in Table 1] 
in patients adhering to lifestyle modifications and to an appropriate regimen of three or 
more antihypertensive drugs from different pharmacological classes including a diuretic, 
in the absence of a secondary cause of hypertension [Calhoun 2008, Williams 2018].  
The definition of uncontrolled BP varies with the method of measurement, as shown in 
Table 1. 
Table 1 
BP thresholds for the definition of uncontrolled BP (i.e., 
hypertension) 
Method of measurement 
SBP and/or DBP (mmHg) 
Automated office BP measurement* 
≥ 135/85* 
Ambulatory BP monitoring** 
-
Daytime (or awake)
≥ 135/85** 
-
Night time (or sleep)
≥ 120/70** 
-
24 hour
≥ 130/80** 
Home BP monitoring** 
≥ 135/85** 
* The term automated office BP measurement (AOBPM) refers to BP measurement obtained using a fully automated
electronic sphygmomanometer that records multiple BP readings with the patient resting undisturbed in a quiet place
without medical staff being present [Leung 2017, Myers 2010].
** Extracted from [Williams 2018]. 
ABPM = ambulatory blood pressure monitoring; AOBPM = automated office blood pressure measurement; BP = blood 
pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure. 
In order to minimize the rate of screening and RI failures, the investigator is encouraged to 
have a comprehensive medical history available for patients they intend to screen. Review 
of subject charts allows the identification of apparent RHT and helps avoid inappropriate 
subject screening. Subjects with any of the chronic conditions mentioned in the exclusion 
criteria list [see Section 4.4] should not be considered for screening. 
This study will enroll adult male and female subjects with a diagnosis of true RHT 
[Section 1.1 and Section 4.2] having a mean SiSBP measured by AOBPM ≥ 140 mmHg. 
This higher threshold (as compared to the table above) was chosen in order to minimize 
screening failures that are likely to occur following the switch to the standardized 
background antihypertensive therapy. The BP randomization criterion will also be mean 
trough SiSBP ≥ 140 mmHg in order to increase the sensitivity of the study to observe 
treatment effects. 


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4.2 Rationale for the selection of the study population 
Among the hypertensive population, RHT was selected as the targeted study population 
[see Section 4.1]. No antihypertensive therapy has been specifically developed and 
approved for the treatment of this population. Furthermore, all existing antihypertensive 
therapies used as fourth-line therapy in this population have some limitations with respect 
to adverse drug reactions. This is one of the major causes of treatment discontinuation. 
This, consequently cause uncontrolled BP which is one of the main reasons for increased 
cardiovascular outcomes [Thomopoulos 2016a, Thomopoulos 2016b]. Hence, there is an 
unmet need for this vulnerable and complex patient population who are at high 
cardiovascular risk.  
In this study, subjects with true RHT are included in order to demonstrate the efficacy, 
durability of the effect, and safety of aprocitentan in a hypertensive population with high 
medical need. Subjects with “pseudo” or “apparent” (terms are used interchangeably) RHT, 
which is far more common than “true” RHT will be excluded from the study.  
The selection criteria for this patient population follow the recommendation of the ESH 
and ESC joint guideline [Williams 2018], the American Heart Association Guideline for 
the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults 
[Whelton 2017], as well as several other national guidelines [Denolle 2014, 
McCormack 2013].  
Subjects with confirmed severe hypertension (grade 3), recent major cardiovascular, renal, 
cerebrovascular medical complications, and heart failure NYHA stage III-IV are excluded 
from the study. This is because these patients could potentially be at greater risk of 
experiencing side effects, and/or their conditions could interfere with the evaluation of the 
treatment effect, study assessments and interpretation of study results.  
4.3 Inclusion criteria 
For inclusion in the study, the subject must fulfill all of the following inclusion criteria at 
the specified study visits. It is not permitted to waive any of the criteria for any subject: 
Screening criteria 
1.
Signed and dated ICF prior to any study-mandated procedure.
2.
Male and female subjects; 18 years (or year of country specific majority) or older.
3.
Historical documentation in the subject’s medical records of uncontrolled BP
despite at least 3 background antihypertensive medications within 1 year before
screening visit.
4.
Treated with at least 3 antihypertensive therapies of different pharmacological
classes for at least 4 weeks before the screening visit (Visit 1).


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5.
Mean SiSBP ≥ 140 mmHg measured by AOBPM at screening visit.
6.
Documentation in the subject’s medical records of diagnosis of RHT according to
the site’s medical practice:

Exclusion of secondary causes of hypertension (e.g., serum aldosterone,
plasma renin activity, duplex/doppler ultrasonography, computer tomography
angiography assessments are performed to exclude the secondary causes of
hypertension [Rimoldi 2013]),

Adherence to medication (e.g., how the adherence was checked and/or
monitored) to eliminate apparent RHT.
7.
A woman of childbearing potential [see definition in Section 4.5.1] is eligible only
if the following applies:

Negative pregnancy test at Screening and at baseline (i.e., end of RI period).

Agreement to undertake pregnancy tests during the study and up to 30 days
after randomized study treatment discontinuation.

Agreement to use methods of birth control as described in Section 4.5 from
Screening up to at least 30 days after randomized study treatment
discontinuation.
8.
Mean trough SiSBP ≥ 140 mmHg measured by AOBPM at the switch from
background antihypertensive medications (i.e., at least 3 medications from different
pharmacological classes]) to the standardized background antihypertensive
therapy.
RI entry criteria 
9.
Switched to the standardized background antihypertensive therapy at least 4 weeks
before the first RI visit.
10.
Mean trough SiSBP ≥ 140 mmHg measured by AOBPM.
Randomization criteria (end of RI)
11.
Stable dose of the standardized background antihypertensive therapy for at least
1 week before Day –1 (end of the RI period).
12.
Mean trough SiSBP ≥ 140 mmHg measured by AOBPM.
13.
Subjects demonstrating ≥ 80% compliance (pill counting) to study treatment
(i.e., placebo) as well as ≥ 80% compliance (pill counting) to the standardized
background antihypertensive therapy during the RI period.
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria at the specified study visits. 
It is not permitted to waive any of the criteria for any subject: 


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Screening period criteria 
Disease/condition: 
1. 
Pregnant or lactating subjects.  
2. 
Apparent/pseudo RHT due to white coat effect, medical inertia, poor therapeutic 
adherence, or secondary causes of hypertension (not including obstructive sleep 
apnea).  
3. 
Confirmed severe hypertension (grade 3) defined as mean SiSBP ≥ 180 mmHg 
and/or SiDBP ≥ 110 mmHg measured by AOBPM at two different time points. 
The BP re-measurement can be during the screening visit (e.g., after at least 3 h), 
or at the next planned visit, or at an unscheduled visit. The time of re-measurement 
is at the investigator’s discretion, taking into consideration the subject’s medical 
history. 
4. 
Known and documented transient ischemic attack, stroke, unstable angina or MI 
within 6 months prior to Screening. 
5. 
Clinically significant unstable cardiac disease at screening or in the past in the 
opinion of the investigator, e.g., uncontrolled symptomatic arrhythmia, atrial 
fibrillation, congestive heart failure NYHA stage II with relevant mitral valve 
insufficiency and/or aortic stenosis, congestive heart failure NYHA stage III or IV.  
6. 
Severe renal insufficiency defined as an eGFR per the CKD Epidemiology 
(CKD-EPI) collaboration creatinine equation < 15 mL/min/1.73 m2.  
7. 
Type 1 DM. 
8. 
Subjects working night shifts.  
A maximum of 2 night shifts per week is permitted except within 3 days prior to a 
study visit. Night shifts are not allowed during visits at which ABPM is recorded. 
9. 
Any known factor, disease or clinically relevant medical or surgical conditions that, 
in the opinion of the investigator, might put the subject at risk, interfere with 
treatment compliance, study conduct or interpretation of the results. 
10. 
Known concomitant life-threatening disease with a life expectancy < 18 months of 
Screening. 
Treatments: 
11. 
Treatment with any medication which may affect BP [see Appendix 1] and/or 
treatment with high dose of loop diuretics (i.e., furosemide greater than 80 mg/day, 
or equivalent dosage of other loop diuretics).  
12. 
Treatment with any other ERAs.  
13. 
Contraindication and/or known hypersensitivity to any of the three components of 
the standardized background antihypertensive therapies (fixed combination of CCB 


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[amlodipine], ARB [valsartan] and diuretic [HCTZ]) according to their labels or 
drugs of the same class, or to any of the excipients. 
14.
Known hypersensitivity to aprocitentan or drugs of the same class, or any of the
excipients.
15.
Treatment with another investigational treatment within 3 months prior to
Screening.
16.
Laboratory assessments based on central laboratory

ALT or AST > 3 times the upper limit of normal range, or severe hepatic
impairment.

Hemoglobin < 100 g/L.

NT-proBNP ≥ 500 pg/mL.
If one of these criteria is not met based on central laboratory report, a re-test must 
be performed before Visit 2 (e.g., at the next screening visit, or at an unscheduled 
visit). If the value is confirmed, the subject must discontinue from screening.  
RI period exclusion criteria 
17.
Confirmed severe hypertension (grade 3) defined as mean SiSBP ≥ 180 mmHg
and/or SiDBP ≥ 110 mmHg measured by AOBPM at two different time points.
The BP re-measurement can be during the first RI Visit (e.g., after at least 3 h), or at the 
next planned visit, or at an unscheduled visit. The time of re-measurement is at the 
investigator’s discretion, taking into consideration the subject’s medical history. 
Randomization exclusion criteria 
18.
Laboratory assessments based on local laboratory.

ALT or AST > 3 times the upper limit of normal range.

Hemoglobin < 100 g/L.

eGFR per the CKD-EPI creatinine equation < 15 mL/min/1.73 m2.
At any time between Screening and Randomization the investigator/delegate must verify 
that the subject does not fulfill the exclusion criteria checked at the screening visit (as 
applicable).  
4.5 Criteria for women of childbearing potential 
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 

Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy,


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
Postmenopausal (defined as 12 consecutive months with no menses without an
alternative medical cause [ICH M3 definition]),

Premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome,
uterine agenesis,
Childbearing potential status will be assessed at each visit and recorded in the electronic 
case report form (eCRF). 
4.5.2 Acceptable methods of contraception 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the eCRF.  
Note: The documentation of method of contraception can be based on the site personnel’s 
review of the subject’s medical records, medical examination or medical history interview 
of the subject. 
The use of one of the following options is regarded as a highly effective method of 
contraception: 


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If hormonal contraception is one of the methods used then it must have been initiated at 
least 4 weeks prior to the screening visit (Visit 1) [see Section 5.2.3]. 
Option 3: vasectomized partner is a highly effective birth control method provided that the 
partner is the sole sexual partner of the woman of childbearing potential trial participant 
and that the vasectomized partner has received medical assessment of the surgical success. 


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5 
TREATMENTS 
5.1 Study treatment 
This section applies to study treatment (aprocitentan/placebo). The standardized 
background antihypertensive therapy is described in Section 5.2.2. 
5.1.1 Investigational treatment and matching placebo 
Aprocitentan is currently available for clinical study use as identical tablets of 12.5 and 
25 mg containing aprocitentan and inactive excipients.  
Placebo tablets will be identical in appearance to the aprocitentan tablets, and will contain 
inactive excipients. 
5.1.2 Study treatment dosing and rationale  
For this confirmatory study in RHT, dosages of 12.5 and 25 mg (o.d.) are selected. The 
rationale has been provided in Section 1.2.4. 
5.1.3 Study treatment administration  
Study treatment is supplied in bottles containing 36 tablets to cover a 4-week treatment 
period accounting for one extra week (if needed). 
The subjects must be instructed to take one tablet from the bottle orally o.d. irrespective of 
food intake every morning and not to take it on the morning of study visit days. On the day 
of the study visits, study treatment must be administered only after the completion of the 
visit assessments as indicated in Section 7.2.  
The study personnel must remind subjects at each visit of the study treatment intake 
requirements. The reminders must be documented in the subject’s chart. 
5.1.4 Treatment assignment 
After the informed consent has been signed the investigator/delegate gets a subject number 
through the Interactive Response Technology (IRT) system at Visit 1 (screening visit).  
During the screening period, subjects will be switched to the standardized background 
antihypertensive therapy [see Section 5.2.2], which will be dispensed via the IRT system. 
At the first RI visit the investigator/delegate contacts the IRT system to get a study 
treatment number (i.e., bottle number) for the 4 weeks of the RI period. In the RI period all 
subjects will receive placebo in a SB fashion.  
At Visit 4 / Randomization (Day 1) the investigator/delegate contacts the IRT system to 
randomize the subject to aprocitentan 12.5 mg, aprocitentan 25 mg or placebo in a 


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1:1:1 ratio. The IRT system assigns a randomization number to the subject and a bottle 
number to match the treatment arm assigned by the randomization list.  
At the end of the DB part (Week 4) the investigator/delegate contacts the IRT system to 
get the treatment number (i.e., bottle number) for the SB aprocitentan part. All subjects in 
this period will be assigned to 25 mg aprocitentan.  
At the end of the SB treatment part (Week 36), the investigator/delegate contacts the IRT 
system to re-randomize the subject to aprocitentan 25 mg or placebo in a 1:1 ratio. The 
re-randomization will be stratified by randomized treatment in the DB part, which will not 
be revealed. The IRT system assigns a (scrambled) re-randomization number to the subject 
and a bottle number to match the treatment arm assigned by the re-randomization list. 
The IRT system is handled by an external independent vendor which will generate two 
randomization lists, one for the DB part and another for the DB-WD part. 
5.1.5 Blinding 
This study will have two SB parts: the SB placebo RI period prior to Randomization and 
the SB aprocitentan part of 32 weeks. Accordingly, study personnel must not inform the 
subject of the treatment received during these parts. 
Parts 1 (DB) and 3 (WD-DB) of the study will be performed in a DB fashion. The 
investigator and study personnel, the subjects, the Clinical Research Associates (CRAs), 
sponsor personnel, and vendor/CRO personnel involved in the conduct of the study will 
remain blinded to the study treatment received by the subjects during the DB treatment 
periods until study closure. To ensure adequate supply of study treatment, the IRT vendor 
personnel responsible for clinical study supply distribution and the sponsor individuals 
contributing to clinical supply distribution will need to be unblinded at subject level and 
depot level, respectively. These persons will be clearly identified, their unblinding will be 
documented in the trial master file, and they will not take part in any Clinical Trial Team 
(CTT) meetings after study set-up has been completed. 
Until the time of unblinding for final data analysis, the randomization list will be kept 
strictly confidential, and accessible only to IRT vendor and sponsor authorized persons 
(i.e., Pharmaceutical Development department, Bioanalytical Laboratory group, ISAC and 
IDMC), who are not involved in the conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment bottles will be packaged in the same way. 
To minimize the possibility of systematic unblinding, the PK results will be 
communicated/transferred by the Bioanalytical Laboratory Group to the sponsor and CRO 
personnel involved in the conduct of the study only after database lock. 


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5.1.6 Unblinding  
5.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
lock, in accordance with the sponsor’s Quality System (QS) documents.  
5.1.6.2 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) see definition in 
Section 9.1.3 occurs in a subject participating in the study, the sponsor’s Global Drug 
Safety department will request the unblinding of the treatment assignment to meet 
regulatory reporting requirements. 
The treatment assignment will not be communicated to site personnel or subjects, or to the 
sponsor CTT or any vendor/CRO personnel involved in the conduct of the study. 
Unblinded SUSAR information will be provided to respective health authorities and 
Independent Ethics Committees / Institutional Review Boards (IECs/IRBs) only. SUSARs 
will be reported to investigators in a blinded fashion. 
5.1.6.3 Emergency procedure for unblinding 
The investigator, study personnel, subjects, CRAs, sponsor personnel, and any CRO 
personnel involved in the conduct of the study must remain blinded to the subject’s 
treatment assignment.  
The identity of the study treatment may be revealed only if the subject experiences a 
medical event, the management of which would require knowledge of the blinded treatment 
assignment. In this case, the investigator can receive the unblinded treatment assignment 
through the IRT system. In these situations, the decision to unblind resides solely with the 
investigator. Whenever it is possible, and if it does not interfere with (or does not delay) 
any decision in the best interest of the subject, the investigator is invited to discuss the 
intended unblinding with the sponsor personnel. 
The occurrence of any unblinding during the study must be clearly justified and explained 
by the investigator. In all cases, the sponsor personnel must be informed as soon as possible 
before or after the unblinding. 
The circumstances leading to unblinding must be documented in the hospital charts, the 
Investigator Site File (ISF) and in the eCRF. 
5.1.7 Study treatment supply 
Manufacturing, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, GCP, and any local or national regulatory 
requirements. 


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All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.7.1 Study treatment packaging and labeling 
Study treatment is provided as tablets in childproof bottles. Study treatment is labeled to 
comply with the applicable laws and regulations of the countries in which the study sites 
are located. 
5.1.7.2 Study treatment distribution and storage 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label. The storage conditions must be explained to the 
subject. 
5.1.7.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used, partially used, and unused study 
treatment bottles at each visit. Should the treatment bottle dispensed at a scheduled visit be 
lost or damaged, a replacement bottle can be requested via the IRT system. 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 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. 
5.1.7.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from the sponsor. On an ongoing basis and/or on termination of the study, 
the CRA will collect used and unused treatment kits, which will be sent to the warehouse, 
where the sponsor personnel or a deputy will check treatment reconciliation. In certain 
circumstances, used and unused study treatment containers may be destroyed at the site 
once study treatment accountability is finalized and has been checked by the sponsor 
personnel or the deputy, and written permission for destruction has been obtained from the 
sponsor. 
5.1.8 Study treatment adherence 
Adherence to medications is one of the key elements in the treatment of chronic diseases 
such as hypertension/RHT. In this study, study treatment adherence will be assessed 
throughout the study based on study treatment accountability (tablets count) for study 
treatment and the standardized background antihypertensive therapy, monitoring of the 


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intake of the standardized background antihypertensive therapy by urine analysis, and 
direct observed treatment (DOT) at the four planned ABPM assessments [see 
Section 7.2.2.2]. 
5.1.8.1 Study treatment adherence based on accountability 
The inventory of study treatment and the standardized background antihypertensive 
therapy 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. It is to be recorded by site personnel on the study treatment dispensing and 
accountability log and in the eCRF, and checked by the CRA during site visits and at the 
end of the study. The study treatment accountability log in the eCRF will include at least 
the following information for each study treatment unit (i.e., bottle) dispensed to the 
subject: 

Dispensed bottle (study treatment) / blister or bottle (standardized background
antihypertensive therapy) ID number;

Date dispensed / number of tablets dispensed (pre-populated in eCRF);

Date returned / number of tablets returned.
All supplies, including partially used or empty bottles/blisters must be retained at the site 
until they are verified by the CRA. 
If the subject omits to bring the remaining study treatment to a study visit, at which new 
study treatment will be dispensed [see Table 2 and Table 3], he/she must be instructed to 
not take any tablets from the forgotten study treatment bottle and to return it at the next 
visit.  
For each time interval between two visits (i.e., “period”), the adherence to study treatment 
and, separately, the standardized background antihypertensive therapy based on study 
treatment accountability will be calculated by the sponsor using the following formula: 
Adherence based on study treatment accountability = 
(number of tablets dispensed at visit n – number of tablets returned at Visit n + 1) / number 
of tablets that should have been taken during the period)] × 100 
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). 
Between visits, adherence based on study treatment and the standardized background 
antihypertensive therapy accountability is expected to be at least 80%.  


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Adherence at the end of the RI period is one of the randomization criterion. Subjects with 
adherence values below 80% for study treatment and/or the standardized background 
antihypertensive therapy will be considered as RI failure and cannot be randomized. In 
order to minimize misuse of study medication by the subject (e.g., throwing out tablets 
from the returned bottles) and to properly evaluate this randomization criterion, the study 
staff must not inform the subject about this criterion.  
Adherence values below 80% for the study treatment and/or the standardized background 
antihypertensive therapy without a medical justification (e.g., AE) after the randomization 
visit is considered a protocol deviation, which will be reported as such to the sponsor by 
the CRA. In such cases, the investigator/delegates must discuss and clarify the reasons for 
non-compliance with the subject and take appropriate actions to avoid re-occurrence. This 
discussion must take place prior to providing the next study treatment to the subject. The 
outcome of the discussion must be documented in the source documents. 
5.1.8.2 Standardized background antihypertensive therapy adherence based on urine 
analysis 
Urine samples will be collected throughout the study from initiation of the standardized 
background antihypertensive therapy. The samples must be collected at trough, i.e., before 
taking the study treatment and the standardized background antihypertensive therapy. The 
urine will be analyzed for the presence of valsartan (one of the components of the 
standardized triple combination). The results of urine analysis from each visit will be used 
to discuss the importance of study treatment intake with poorly adherent subjects.  
In such cases, the investigator/delegates must call the subject within 1 week of receiving 
the data to clarify the reasons for non-adherence, and take appropriate actions to avoid 
re-occurrence. The subject must be re-trained on the intake of study treatment and the 
standardized background therapy, and risks associated with uncontrolled BP caused 
potentially by not taking the study treatment as instructed. The date of phone call and main 
points discussed with the subject must be documented in the subject’s chart. 
5.1.9 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments are not permitted. Study treatment may be temporarily 
interrupted in response to an AE, or other reasons (e.g., diagnostic or therapeutic procedure, 
a laboratory abnormality, study treatment forgotten).  
If study treatment is interrupted by the subject for any reason, he/she must immediately 
inform the investigator. Interruptions of study treatment should be no longer than 
7 consecutive days during DB part and DB-WD part. During the SB aprocitentan part the 
interruptions of study treatment could be 14 consecutive days. Otherwise, permanent study 
treatment discontinuation should be considered.  


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All study treatment interruptions must be recorded in the eCRF. 
5.1.10 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or sponsor personnel. The main reason (e.g., AE, hypertension grade 3) must 
be documented in the eCRF. 
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 WD from the study [see Section 8.2]). Although 
a subject is not obliged to give his/her reason for prematurely withdrawing from the 
treatment or the study, it is recommended that the investigator makes a reasonable effort to 
ascertain the reason(s), while fully respecting the subject’s rights. 
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continued administration would be contrary to the best interests of the subject. 
Study-specific criteria for discontinuation of study treatment (aprocitentan/placebo) are 
described in Section 5.1.11. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study, provided that the subject’s consent for this limited participation in the study 
has not been withdrawn.  

If a subject discontinues study treatment during the RI period the subject will be
asked to perform the end of RI visit and a safety FU call 30 (+3) days thereafter. The
standardized background antihypertensive therapy will only be provided until the end
of RI visit. Thereafter, antihypertensive medication(s) should be administered
according to local standard-of-care at the investigator’s discretion.

If a randomized subject discontinues study treatment the subject will be asked to
perform the EOT visit (i.e., Visit 15) as soon as possible after the last dose of study
treatment but, in any case, no later than 7 days and a safety FU visit 30 (+3) days
thereafter. Antihypertensive medication(s) should be administered according to local
standard-of-care at the investigator’s discretion. The standardized background
antihypertensive therapy may be continued until the completion of the safety FU
visit.
The following visits must be performed for subjects who prematurely discontinued
during the DB part and DB-WD part:
–
If a randomized subject discontinues study treatment during the DB part the
subject will be asked to perform the scheduled Week 4 visit. If the scheduled
Week 4 visit is within 7 days of the EOT or safety FU visit, the Week 4 visit can
be skipped.


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–
If a randomized subject discontinues study treatment during the DB-WD part the
subject will be asked to stay in the study and to perform the remaining visits of
the DB-WD period. If a scheduled Week 40, Week 44 or Week 48 visit is within
7 days of the EOT or safety FU visit, this Week 40/44/48 visit can be skipped.
A subject who prematurely discontinues study treatment at any stage, 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. WD from the study and follow-up medical care of subjects withdrawn from the 
study are described in Sections 8.2 and 8.4, respectively. 
5.1.11 Study-specific criteria for interruption / premature discontinuation of study 
treatment  
All the following criteria apply after Randomization. 
5.1.11.1 Hypertension  
If mean SiSBP ≥ 180 mmHg and/or mean SiDBP ≥ 110 mmHg measured by AOBPM, 
i.e., essential hypertension grade 3 [Williams 2018], BP must be re-measured. The BP
re-measurement can be at the next planned visit, or at an unscheduled visit. The time of
re-measurement is at the investigator’s discretion, taking into consideration the subject’s
medical history.
If grade 3 is confirmed by BP re-measurement, the study treatment must be permanently 
discontinued.  
5.1.11.2 Renal failure 
Study treatment must be permanently discontinued in the event of: 

Confirmed (within one week) eGFR< 15mL/min/1.73m2 or

Confirmed (within one week) increase of > 2  from baseline in serum creatinine.
5.1.11.3 Persistent fluid retention 
Study treatment must be permanently discontinued if the symptom(s) of fluid retention are 
not tolerable after increasing the dose of the existing diuretic or the addition of a new 
diuretic [Section 5.2.3.1].  
5.1.11.4 Hemoglobin abnormalities 
In the event of hemoglobin decrease from baseline of > 20 g/L, a hemoglobin retest must 
be performed within one week, with additional laboratory evaluations that include, but are 
not limited to, any of the following:  
Red blood cell cellular indices (mean corpuscular volume [MCV], mean corpuscular 
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC]), reticulocyte 


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count, iron status (iron level, serum ferritin, total iron binding capacity, transferrin 
saturation).  
Study treatment must be permanently discontinued if clinically mandated based on the 
investigator’s judgment, or in any of the following situations:  

A decrease in hemoglobin to < 80 g/L (< 4.9 mmol/L),

A decrease in hemoglobin from baseline of > 50 g/L,

The need for transfusion.
5.1.11.5 Liver aminotransferases abnormalities 
Interruption of study treatment  
Study treatment must be interrupted in the following case: 

Aminotransferases (i.e., ALT and/or AST) ≥ 3 and ≤ 8 × the upper limit of normal
(ULN)
Perform a re-test of aminotransferases (ALT and AST), total and direct bilirubin, and 
alkaline phosphatase within one week. If AST and/or ALT elevation is confirmed, the 
re-test must be performed weekly until the value is within normal range or has returned to 
pre-treatment levels. Interruptions of study treatment are allowed up to 7 consecutive days 
during the DB part and the DB-WD part, and 14 consecutive days during the SB 
aprocitentan part [see Section 5.1.9].  
Aminotransferases, total and direct bilirubin, and alkaline phosphatase levels must be 
monitored weekly after study treatment discontinuation until values return to pre-treatment 
levels or within normal ranges. 
Permanent discontinuation of study treatment 
Study treatment must be permanently discontinued and its re-introduction is not to be 
considered in the following cases:  

Aminotransferases > 8 × ULN.

Aminotransferases ≥ 3 × ULN and associated clinical symptoms of liver injury, e.g.,
nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu like
syndrome (arthralgia, myalgia, fever).

Aminotransferases ≥ 3 × ULN and associated increase in total bilirubin ≥ 2 × ULN.
Aminotransferases, total and direct bilirubin, and alkaline phosphatase levels must be 
monitored weekly after study treatment discontinuation until values return to pre-treatment 
levels or within normal ranges.  


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Other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, cytomegalovirus) 
and/or etiologies (e.g., acetaminophen-related liver toxicity) should be considered and 
ruled out by performing the appropriate tests. To ensure the proper and comprehensive 
evaluation of hepatic events, additional subject data might be collected via the Idorsia 
Global Drug Safety department. 
5.1.11.6 Pregnancy 
At any time during the study, if a subject becomes pregnant, 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. 
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to the signature of the 
ICF. 
A therapy that is study-concomitant is any treatment that is ongoing or initiated after the 
signature of the ICF, or initiated up to 30 days after study treatment discontinuation. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at the 
start of randomized study treatment or is initiated during the randomized treatment period. 
5.2.2 Mandatory concomitant therapy 
During the screening period, at least 4 weeks before the start of the RI period, the 3 or more 
background antihypertensive medications that the subject had at entry in the study must be 
switched to a standardized background antihypertensive therapy which is a triple fixed 
combination of CCB (amlodipine), ARB (valsartan) and diuretic (HCTZ). The dose 
strength must be stable during the RI period.  
Two dose strengths will be available: 10/160/25 and 5/160/25 mg (amlodipine, valsartan, 
HCTZ, respectively). The fixed combination will be provided to all subjects from time of 
the switch until EOS. The selection of the dose strength of the standardized background 
antihypertensive therapy for an individual subject (either 5 or 10 mg) is at the investigator’s 
discretion and may vary during the screening period. It is required to use the maximal 
tolerated dose of the background antihypertensive therapy (i.e., 10 mg amlodipine, if there 
is no tolerability issue) from the start of the RI period. The dose strength must be kept 
stable for at least 1 week before Day –1 (end of the RI period) until the end of DB part (i.e., 
Week 4) and during the DB-WD part. The dose strength might be adjusted later on, during 
the SB aprocitentan part. If the highest dose of amlodipine (i.e., 10 mg) cannot be used, the 
reason should be documented in the eCRF. If standardized background antihypertensive 
therapy is interrupted by the subject for any reason, he/she must immediately inform the 
investigator. All interruptions must be recorded in the eCRF. 


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The standardized background antihypertensive therapy is supplied in blisters or bottles to 
cover the period up to the next scheduled visit. The subjects must be instructed to take one 
tablet orally o.d. irrespective of food intake every morning and not to take it on the morning 
of study visit days. The standardized background antihypertensive therapy will be supplied 
to all subjects by the sponsor and will be dispensed at the same time as the study treatment 
via the IRT system [see Section 5.1.4]. The protocol-mandated dispensing procedures for 
the standardized background antihypertensive therapy may be different in some countries 
depending on the number of tablets in one blister/bottle. In such a case, the detail on 
dispensing procedure will be provided in the site file.  
Subjects are asked to return all used, partially used, and unused bottles/blisters at each visit. 
It must be kept in an appropriate, secure area and stored according to the conditions 
specified on the label. The storage condition must be explained to the subject. 
Treatment adherence will be performed as study treatment, for details see Section 5.1.8. 
5.2.3 Allowed concomitant therapy 
Treatments considered necessary for the subject’s well-being and not categorized as 
forbidden concomitant medications are allowed during the study and must be documented 
in the medical charts.  
The following therapies are allowed with the provision that they have been initiated and 
the dose stable at least 4 weeks prior to the screening visit and that the dose is kept stable 
until the EOT:  

Beta blockers;

Alfuzosin and tamsulosin (alpha-adrenergic receptor blockers) for prostatic
symptoms;

Hormonal contraceptives;

Estrogen-replacement treatment;

Sodium-glucose co-transporter 2 inhibitors;

Erythropoiesis-stimulating agents;

Psychiatric drugs;

For selective serotonin reuptake inhibitors (SSRIs) and anxiolytics the instruction
provided in the next paragraph must be followed;

Low dose acetylsalicylic acid for prevention of cardiovascular disease.
In addition, the following therapies are allowed with the provision that they have been 
initiated at least 4 weeks prior to the screening visit and that the dose is kept stable until 
the end of DB part (i.e., Week 4):  


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
Non-steroidal anti-inflammatory drugs;

SSRIs and anxiolytics (such as benzodiazepine).
After Week 4 (end of DB part) these medications can be used, if necessary, for the subject’s 
well-being.  
5.2.3.1 Antihypertensive rescue medication 
In the SB aprocitentan part and DB-WD part (i.e., part 2 and part 3, respectively), if, in the 
investigator’s opinion, the BP of a subject is not sufficiently controlled, antihypertensive 
rescue medication can be added according to local medical practice to the study treatment 
and the standardized background antihypertensive therapy, but only after confirmation of 
the BP value by a second measurement. The second measurement should be performed 
either at the next planned visit or at an unscheduled visit at the investigator’s discretion. In 
addition, the urine analysis for detection of valsartan must confirm adherence to the 
standardized background antihypertensive therapy, otherwise additional antihypertensive 
medication should not be added.  
Antihypertensive rescue medication is not allowed in the DB part of the study. 
Antihypertensive rescue medication must be recorded in the eCRF. 
5.2.3.2 Diuretics for fluid retention 
After Randomization, the dose of the existing diuretic (HCTZ) can be increased or a new 
diuretic can be added in the event of fluid retention judged by the investigator to be 
clinically relevant. The investigator’s judgment should be guided by biomarkers such as 
subject’s weight gain, NT-proBNP, and/or signs and symptoms. 
The fluid retention must be reported as an AE in the eCRF. In this case fluid retention must 
be reported as the indication for the diuretic. If the symptom(s) of fluid retention are not 
tolerable the subject must discontinue the study treatment. 
5.2.4 Forbidden concomitant therapy 
To avoid concomitant administration of medications that would either compete with the 
same targeted receptors as aprocitentan, have an uncertain effect on BP, or trigger BP 
reduction or elevation, the following concomitant therapies are forbidden from the 
screening visit until the EOT visit:  

Any drug which may affect BP (except rescue and allowed medications described
above), see Appendix 1;

ERAs;

Investigational drug, other than ID-080A301 study treatment.


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If a randomized subject takes any of these forbidden medications, the investigator/delegate 
must contact the sponsor for further follow-up actions, including stopping/interrupting 
study treatment as appropriate.  
For subjects who permanently discontinued study treatment the investigator/delegate will 
explain to subjects what treatment(s) / medical care is necessary and available according 
to local practice. 
5.2.5 Reporting of previous / concomitant therapy in the eCRF  
The generic name, start/end dates of administration, route, dose regimen, and indication 
will be recorded in the eCRF. 
5.2.5.1 Antihypertensive therapies 
All antihypertensive therapies stopped at Screening and/or ongoing at Screening will be 
recorded in the eCRF, i.e., start/end dates of administration, reason for discontinuation and 
dose regimen. 
Antihypertensive treatments stopped in the last 12 months prior to Screening, start/end 
dates, dose regimen, and reason for discontinuation should be available in the hospital chart 
but will not be reported in the eCRF. 
If a new antihypertensive therapy other than mandatory background therapy (i.e., the fixed 
combination of CCB, ARB and diuretic) and study treatment is (re-)initiated during the 
course of the study, the date of initiation, dose and detailed reason for (re-)initiation must 
be recorded in the eCRF.  
5.2.5.2 Other therapies 
The use of all other study-concomitant therapy (including traditional and alternative 
medicines, e.g., plant-, animal-, or mineral-based medicines) must be recorded in the eCRF. 
Any other previous therapy must be recorded in the eCRF if discontinued less than 30 days 
prior to signing of the ICF. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the change from baseline to Week 4 of DB treatment in 
mean trough SiSBP measured by AOBPM. 
Baseline is defined as the last available measurement before the start of DB treatment. 


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6.1.2 Secondary efficacy endpoints 
The key secondary efficacy endpoint is the change from Week 36 to Week 40 of DB-WD 
treatment in mean trough SiSBP measured by AOBPM. 
The other secondary efficacy endpoints are: 

Change from baseline to Week 4 of DB treatment in mean trough SiDBP measured by
AOBPM;

Changes from baseline to Week 4 of DB treatment in 24 h mean SBP and DBP
measured by ABPM;

Change from Week 36 to Week 40 of DB-WD treatment in mean trough SiDBP
measured by AOBPM;

Changes from Week 36 to Week 40 of DB-WD treatment in 24 h mean SBP and DBP
measured by ABPM.
6.1.3 Other efficacy endpoints 

Changes from baseline to Week 2 of DB treatment in mean trough SiSBP and SiDBP
measured by AOBPM;

Changes from baseline to Week 4 in daytime and nighttime mean SBP and DBP;

Changes from Week 36 to Week 38, Week 44 and Week 48 of DB-WD treatment in
mean trough SiSBP/SiDBP measured by AOBPM;

Changes from Week 36 to Week 40 in daytime and nighttime mean SBP and DBP;

Changes from baseline to all assessed time points of DB, SB and DB-WD parts in
urine albumin-to-creatinine ratio (UACR);

Discontinuation of randomized study treatment due to confirmed grade 3 (i.e., mean
SiSBP/SiDBP ≥ 180/110 mmHg, respectively) hypertension.

Initiation of antihypertensive rescue medication in the SB aprocitentan part or DB-WD
part.
6.2 Safety endpoints 

Treatment-emergent AEs;

Treatment-emergent SAEs;

Treatment-emergent AEs leading to premature discontinuation of study treatment;

Treatment-emergent MACEs, defined as cardiovascular death, non-fatal MI, and
non-fatal stroke [EMA 2016b]. Only those events confirmed by the CAC will be
considered;


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
Treatment-emergent MACE-plus, defined as cardiovascular death, non-fatal MI,
non-fatal stroke and hospitalization for heart failure; only those events confirmed by
CAC will be considered;

Increase of the dose of an existing diuretic or addition of a new diuretic due to fluid
retention;

Changes from baseline to each visit up to EOS in body weight and HR;

Treatment-emergent marked laboratory abnormalitiesa at each visit up to EOS;

Changes from baseline to each visit up to EOS in laboratory variables;

Changes from baseline to each visit up to EOS in 12-lead ECG variables.
 a The selection of marked abnormalities considered for the analyses will be based on 
standard definitions and described in the Statistical Analysis Plan (SAP). 
6.3 Pharmacokinetic endpoints 

Trough plasma concentration of aprocitentan at Week 4 of the DB part.
6.4 Biomarker endpoints

Characterization of ET system activity biomarkers (e.g., CT-proET-1, ET-1, ET-3,
renin and aldosterone) and NT-proBNP in the study population at Screening as well
as at the end of RI;

Changes from baseline to Week 4 in these biomarkers;

Changes from baseline to time points up to Week 36 in NT-proBNP, mid-regional
pro-atrial natriuretic peptide (MR-proANP) and Troponin I;

Changes from Week 36 to time points up to Week 48 in NT-proBNP, MR-proANP
and Troponin I.
6.5 Rationale for primary and secondary endpoints 
Hypertension is an important public-health challenge worldwide. There is global 
recognition that favorable effects of antihypertensive agents on BP reduction translate into 
morbidity/mortality benefits, as acknowledged in the FDA’s approved labels for all 
antihypertensive products. BP is a valid surrogate endpoint accepted by regulatory bodies 
for the development of antihypertensive agents [Desai 2006].  
SBP is the main accepted target nowadays, especially in a population with an average age 
of around 61 years old and above. Landmark therapeutic clinical trials as SPRINT and 
PATHWAY-2 are based on SBP as the primary endpoint [Wright 2015, Williams 2015]. 
SBP measured by AOBPM is the primary and main secondary endpoint of this study. DBP 
is correlated with SBP and will be analyzed as a secondary endpoint.  


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The AOBPM was chosen as the method for measuring the primary efficacy endpoint and 
main secondary endpoint, based on the results of the recently completed Phase 2 study. 
AOBPM minimizes the white coat effect [Myers 2010] and allows immediate 
teletransmission of the BP readings and therefore offers better monitoring. In addition, 
AOBPM has less missing data compared to ABPM, which is known to be a burden for 
subjects. ABPM will be used for 24 h SBP/DBP recording as secondary endpoint. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits 
The study visits, their respective time windows and the assessments to be performed at 
each visit are listed in Table 2 and Table 3. 
7.1.1 Screening/re-screening 
7.1.1.1 Screening 
The date of the screening visit is the date when the ICF is signed see Section 12.3 for the 
informed consent procedure.  
The subjects who agree to participate in the study and the investigator/delegate must sign 
the ICF prior to any study-related assessment or procedure. 
If the signing of the ICF and performance of the first study-specific procedures or 
assessments take place on the same day, it must be clear from the source documents that 
informed consent was obtained prior to any study-specific procedures being performed. 
If a study-specific procedure or assessment has been performed as part of routine 
assessments on the day of the screening visit prior to the subject signing the ICF, such 
procedure or assessment may be used and does not have to be repeated (e.g., vital signs). 
In such cases, it must be clear from the source documents when and for which reason the 
assessment was done prior to the signing of the ICF. 
For convenience reasons, study-specific procedures or assessments can take place on 
different days/visits during the screening period. 
Subjects who sign the ICF when the enrollment target has already been met may still be 
randomized. 
7.1.1.2 Re-screening 
Subjects who did not meet the criteria for participation in the study (i.e., screen failure) 
may be re-screened once, if the reason for non-eligibility was transient (e.g., abnormal 
laboratory test, insufficient time for optimization [i.e., maximal tolerated dose] of 
background antihypertensive medications, insufficient time window for allowed 


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medications, BP measurement technical issue[s]). Subjects who have switched to the 
standardized background antihypertensive therapy cannot be re-screened. 
A new ICF must be signed prior to re-screening the subject if more than 3 months have 
elapsed since the first ICF signature. All screening assessments should then be repeated at 
the time of re-screening. 
7.1.2 Placebo RI period 
The RI period is a SB placebo treatment period. The study staff must not inform the 
subjects about the treatment they are receiving during this period. 
If at any time during the RI period a subject must be discontinued from study treatment 
due to any reason, the end of RI visit must take place as soon as possible and no later than 
7 days after the last dose of RI study treatment (i.e., placebo) and a safety FU call 30 (+ 3) 
days thereafter. The reason of the RI failure must be recorded in the eCRF.  
7.1.3 Randomized treatment period 
At end of RI visit (Day –1) all eligibility criteria for randomization must be checked [see 
Section 4.3]. If these criteria are met, the subject will be randomized the following day.  
In case of premature discontinuation of randomized study treatment, the EOT visit must 
take place as soon as possible and no later than 7 days after the last dose of randomized 
study treatment and a safety FU visit 30 (+ 3) days thereafter.  
Subjects who prematurely discontinue randomized study treatment for any reason will not 
be replaced. 
7.1.4 Unscheduled visits 
Unscheduled visits may be performed at any time during the study and corresponding data 
will be recorded in the eCRF. Body weight, BP, and HR must be measured and recorded 
in the eCRF at each unscheduled visit. These assessments are not required in case of re-test 
of laboratory parameters only. PK and biomarker sampling must not be performed during 
unscheduled visits unless the reason for this unscheduled visit is to retest NT-proBNP for 
confirmation of eligibility criterion at screening. Other assessments are performed at the 
discretion of the investigator.  
After an unscheduled visit, the regular scheduled study visits must continue according to 
the planned visit and assessment schedule. 


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Table 2 
Visit and assessment schedule up to randomization 
PERIODS 
Name / Duration 
Screening 
4-12 weeks 
Run-in  
4 weeks 
 
VISITS1 
Number 
1 
1.112 
2 
3 
4 
Time 
Week -16 to Week -8 
Week -8 
at the latest 
Week -4 
Week -2 
End of Run-in 
Randomization 
Additional visits as needed 
Day -28 
( 4 d) 
Day -14 
( 2 d) 
Day –1 
Day 1 
Informed consent 
X 
 
 
 
 
 
Eligibility including confirmation of diagnosis of true RHT 
X 
X 
X13 
 
X15 
 
Demographics / Medical history 
X 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Body weight, height2 
X 
X 
X 
X 
X16 
 
12-lead ECG3 
X 
 
 
 
X16 
 
Laboratory tests4  
X 
 
 
 
X16,17 
 
Serum pregnancy test 
X 
X 
X 
 
X16,17 
 
Urinalysis5 
 
 
  
  
X16 
 
Urine sampling to monitor treatment adherence6 
 
 
X6 
X  
X16 
 
AOBPM (incl. HR) 
X 
X 
X 
X 
X 
 
Home BP monitoring7 
  
 
ABPM 
 
 
 
 
X16 
X 
Blood sampling for biomarkers8 
X 
 
 
 
X 
 
Accountability of study treatment and standardized background 
antihypertensive therapy9 
 
 
X 
X 
X16 
 
Dispensing/return of study treatment and standardized background 
antihypertensive therapy10 
 
X 
X14 
 
X 
X 
SAE11 and AE11 
X 
X 
X 
X 
X 
X 


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1 Unscheduled visits may be performed at any time during the study. See Section 7.1.4 for details. 
2 Body weight is measured at each visit with the same weight scale. Height is only measured at Screening. 
3 ECGs are read centrally. 
4 Hematology and clinical chemistry. 
5 For UACR determination. 
6 Urine sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy). For subjects who do not fulfill Run-in eligibility criteria no urine 
sample to be collected. 
7 Upon investigator’s judgment, a home BP monitoring device will be dispensed, if necessary.  
8 Blood sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy), see Section 7.2.5 for details. 
9 Drug accountability (pill counts of study treatment and standardized background antihypertensive therapy). 
10 Study treatment including standardized background antihypertensive therapy should be brought back to each visit. 
11 All AEs and SAEs that occur after signing the informed consent form and up to 30 days after study treatment discontinuation must be reported. 
12 Switch to the standardized background antihypertensive therapy. Visit 1.1 may be at the same day as Visit 1. Additional visits may be performed for further assessments (e.g., to adjust the 
dose of the standardized background antihypertensive therapy, taking urine samples to monitor adherence).  
13 Run-in eligibility criteria. 
14 From this time point onwards the dose of the standardized background antihypertensive therapy must be kept stable. 
15 Randomization eligibility criteria. 
16 For subjects who permanently discontinue prior to Randomization due to any reason or do not fulfill the randomization eligibility criteria, these tests are not mandatory.  
17 Two samples will be drawn: one sample for central laboratory and one sample for local laboratory to measure hemoglobin, creatinine (to determine eGFR), and AST/ALT and to perform a 
pregnancy test to confirm eligibility of subjects for randomization.  
ABPM = ambulatory blood pressure monitoring; AE = adverse event; ALT = alanine aminotransferase; AOBPM = automated office blood pressure measurement; AST = aspartate 
aminotransferase; BP = blood pressure; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HR = heart rate; RHT = resistant hypertension; RI = run-in; SAE = serious 
adverse event; UACR = urine albumin-to-creatinine ratio. 


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Table 3 
Visit and assessment schedule from start of DB Treatment period up to EOS 
PERIODS 
Name / 
Duration 
DB Treatment 
4 weeks 
SB Treatment 
32 weeks 
DB-WD Treatment 
12 weeks 
FU12 
30 days 
VISITS1 
Number 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Time 
Week 2 
Week 4 
Week 6 
Week 12 Week 20 Week 28 
Week 36 
Week 38 
Week 40 
Week 44 
EOT11 
Week 48 
EOS 
(EOT+30 d) 
Day 14 
( 2 d) 
Day 28 
( 2 d) 
Day 
29 
Day 42 
( 2 d) 
Day 84  
( 10 d) 
Day 140 
( 10 d) 
Day 196  
( 10 d) 
Day 252 
( 12 d) 
Day 
253 
Day 266 
( 4 d) 
Day 280 
( 4 d) 
Day 
281 
Day 308 
( 4 d) 
Day 336 
( 4 d) 
Day 366 
(+ 3 d) 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
Body weight2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG3
X 
X 
X 
X 
X 
X 
Laboratory tests4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sampling to monitor treatment adherence6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AOBPM (incl. HR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Home BP monitoring7 
ABPM 
X 
X 
X 
X 
X 
X 
Blood sampling for PK8 
X 
Blood sampling for biomarkers8 
X 
X 
X 
X 
Accountability of study treatment and 
standardized background antihypertensive 
therapy9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing/return of study treatment and 
standardized background antihypertensive 
therapy  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE10 and AE10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 


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1 Unscheduled visits may be performed at any time during the study. See Section 7.1.4 for details. 
2 Body weight is measured at each visit with the same weight scale.  
3 ECGs are read centrally. 
4 Hematology and clinical chemistry including NT-proBNP and serum pregnancy test. During SB aprocitentan part, urine pregnancy tests will be performed monthly (i.e., between scheduled 
visits) at home with kits that are provided to the subject. 
5 For UACR determination. 
6 Urine sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy).  
7 Upon investigator’s judgment, a home BP monitoring device will be dispensed, if necessary.  
8 Blood sampling at trough (i.e., before intake of study treatment and standardized background antihypertensive therapy), see Section 7.2.5 for details. 
9 Study treatment including standardized background antihypertensive therapy should be brought back at each visit for drug accountability (pill counts). 
10 All AEs and SAEs that occur after signing the informed consent form and up to 30 days after study treatment discontinuation must be reported. 
11 Randomized subjects who prematurely discontinue prior to Week 48/Visit 15 should have an EOT visit scheduled no later than 7 days after the last dose of randomized study treatment.  
12 For subjects who discontinued during the RI period, this will be a phone call to collect adverse events and concomitant medications only. 
ABPM = ambulatory blood pressure monitoring; AE = adverse event; AOBPM = automated office blood pressure measurement; BP = blood pressure; DB = double-blind; 
ECG = electrocardiogram; EOT = End-of-Treatment; HR = heart rate; NT-proBNP = N-terminal pro-brain natriuretic peptide; PK = pharmacokinetic(s); RI = run-in; SAE = serious adverse 
event; UACR = urine albumin-to-creatinine ratio. 


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7.2 Study assessments 
The study assessments are listed in Table 2 and Table 3. The assessments that are 
mandatory during a visit are marked with an ‘X’. 
All study assessments performed during study visits (scheduled or unscheduled) are to be 
done by the investigator/delegate and are recorded in the eCRF, unless otherwise specified. 
The following order of assessments is recommended: 

Date and time of the last study treatment and standardized background
antihypertensive therapy intake (i.e., the day prior to each study visit),

AOBPM and HR measurements at trougha;

Blood sampling including PK and biomarker samples at trougha;

Urine sampling including sampling for drug monitoring at trougha;

Physical examination (including assessment of AEs/SAEs), and body weight;

ECG;

Start ABPM;

Intake of the study treatment and standardized background antihypertensive therapy at
the site in the presence of the study staff.
a Before taking the study treatment and the standardized background antihypertensive 
therapy.  
If the Principal Investigator (PI) delegates any study procedure/assessment for a subject 
(e.g., ECG, blood / urine sampling) to an external facility, he/she should inform the sponsor 
to whom these tasks are delegated. The set-up and oversight will be agreed upon with the 
sponsor. The supervision of any external facilities remains the responsibility of the PI. 
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available prior to the screening of 
the first subject:  

BP monitoring devices (i.e., AOBPM and ABPM);

Body weight scale;

ECG devices;

Temperature measurement devices for study treatment storage area and laboratory
sample storage (e.g., freezer);

Calibration certificates of other equipment must be available as per local requirements.


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7.2.1 Baseline demographics and disease characteristics 
Demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race, ethnicity (if allowed in the country), weight and height. Relevant medical 
history / current medical conditions (e.g., chronic and ongoing acute conditions, serious 
past conditions) present before signing of the ICF will be recorded in the eCRF. In 
particular, the following conditions must be considered: DM, angina pectoris, heart failure, 
CKD, obstructive sleep apnea syndrome. Where possible, main diagnoses, instead of 
symptoms, will be recorded.  
7.2.1.1 Hypertension history  
True RHT disease characteristics, evidenced by documentation in the subject charts, as 
defined below will be recorded at Screening:  

Date of first diagnosis of hypertension;

Secondary causes of hypertension that have been excluded;

Current antihypertensive medications; i.e., ongoing at Visit 1 and stopped or modified
if required at this visit.
7.2.1.2 Data to be collected for screening failure subjects 
Blood samples for biomarker evaluation must be collected. The following data will be 
recorded in the eCRF if available:  

Date / time of ICF signature;

Demographics (age, sex, race and ethnicity);

Medical history;

Reason for screen failure and associated assessments, if applicable;

Antihypertensive medications; i.e., ongoing at Visit 1;

All AEs and SAEs that occur after signing the ICF;
7.2.2 Efficacy assessments
7.2.2.1 Unattended automated office blood pressure measurement (AOBPM)
Accurate measurement of BP is essential to diagnose subjects with RHT and demonstrate 
the BP lowering effect of aprocitentan in true RHT subjects.  
Fully automated BP measurement has several advantages over manual BP measurements, 
especially in routine clinical practice, by virtually eliminating office-induced increases in 
BP (i.e., white coat effect), improving accuracy, minimizing observer error, and providing 
a more standardized measurement technique [Myers 2010]. Therefore, BP will be 
measured throughout the study with an automatic oscillometric sphygmomanometer which 
will be provided to each site by the central BP laboratory. 


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At each study visit, BP will be measured non-invasively by the provided AOBPM device, 
which records multiple sitting BP readings, with the subject resting undisturbed, alone 
(unattended) in a quiet place. At each assessment, SiSBP and SiDBP will be measured 
using a pre-defined number of readings with preset time interval between them (timed from 
the start of one reading to the start of the next one). The BP device/system generates the 
average of the readings for SiSBP and SiDBP.  
BP must always be measured at trough (i.e., before taking the study treatment and the 
standardized background antihypertensive therapy) at around the same clock time. In case 
an unscheduled visit is performed, BP must be measured using the AOBPM device. 
The AOBPM device must be managed by qualified personnel and whenever possible, the 
same person should use the BP device for a given subject at each visit. It should be 
attempted to perform BP measurements at each visit always using the same arm of the 
subject and the appropriate cuff size, as determined during Screening.  
Details on BP procedure including device to be used, subject preparation (e.g., arm 
selection, arm position, cuff size) will be provided in the BP laboratory manual and will 
follow the American Heart Association guidelines / Canadian Education Program on 
Hypertension [Pickering 2005, Daskalopoulou 2012]. AOBPM data will be electronically 
transferred to the central BP laboratory and subsequently to the sponsor. 
Standing BP measurement  
BP must also be measured in the standing position to monitor orthostatic hypotension [see 
Section 7.2.3.1.1]. Standing SBP/DBP is measured twice, with the AOBPM device, 
approximately one and three minutes after standing.  
Pulse rate  
Pulse rate will be measured at each visit, at the same time as BP measurements, with the 
AOBPM device, in a sitting position. The last pulse rate measurement will be used for 
analysis.  
7.2.2.2 Ambulatory blood pressure monitoring  
ABPM is performed over a 24 h period with the ABPM device set to record BP at a 
pre-defined inflation sequence over the 24 h period at the following visits:  
 
Baseline: At the end of the SB placebo RI period, i.e., Visit 4 / Day –1.  
 
End of DB part: At Visit 6 / Week 4 (Day 28, ± 2 days) 
 
End of the SB aprocitentan part: At Visit 11 / Week 36 (Day 252, ± 12 days). 
 
During the DB-WD part: At Visit 13 / Week 40 (Day 280, ± 4 days)  


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At visits during which ABPM assessments must be performed, the subject must go to the 
site on 2 consecutive days. On the first day after all visit assessments have been performed, 
the ABPM device will be applied to the subject. Thereafter, the subject will take the study 
treatment at the site, in the presence of study personnel (i.e., DOT). The following day 
(i.e., second day), the subject will come back to site to have the ABPM device removed. 
The ABPM device will be provided to each site by the central BP laboratory for the 
duration of the study. ABPM data will be electronically transferred to the central BP 
laboratory and subsequently to the sponsor. 
Details on ABPM procedure (installation, recording and transfer of data) including subject 
preparation will be provided in the BP laboratory manual. 
7.2.2.3 Home blood pressure measurement  
Each site will be provided with home BP monitoring devices. These can be lent to the 
subjects for the entire duration of the study, upon investigator’s judgment, to monitor BP 
at home, if necessary.  
The following instructions must be given to subjects who receive a home BP device:  
 
Explain how to use the device to measure the BP; 
 
Explain to measure BP if there are severe symptoms related to hypertension like 
headache, vomiting, nose bleeding, or symptoms related to orthostatic hypotension 
e.g., light-headedness, pre-syncope, dizziness, as follows:  
– Sit in a calm place for 5 minutes  
– Measure the SBP/DBP:  
o Three readings within 5–10 minutes in the morning before taking your study 
medications  
o Three readings within 5–10 minutes in the evening  
– Record the SBP/DBP values, time of measurement and time of study treatment 
intake in the subject’s card, which will be provided with the device;  
– Measure the BP as described above for 3 days in a row; 
– If the symptoms are still present on the third day, contact the site.  
The data recorded by the subject at home will be filed in the hospital charts. It will not be 
recorded in the eCRF or transferred to the sponsor.  
The subject must give back the device at the EOS.  
7.2.3 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 


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7.2.3.1 Vital signs 
7.2.3.1.1 Orthostatic hypotension 
At each study visit, standing and sitting SBP and DBP will be measured with the AOBPM 
device [see Section 7.2.2.1].  
Symptomatic orthostatic hypotension is defined as a SBP decrease of ≥ 20 mmHg or a DBP 
decrease of ≥ 10 mmHg from sitting to standing position, with symptoms of cerebral 
hypo-perfusion (e.g., light-headedness, dizziness, pre-syncope). The last sitting BP values 
(SBP and DPB) measured by AOBPM are compared to the last measured standing BPs.  
Symptomatic orthostatic hypotension must be recorded as an AE in the eCRF. 
7.2.3.2 Physical examination 
Physical examination at Screening includes the examination of the general appearance, 
heart, lungs, abdomen, skin, extremities/peripheral vascular assessment, eyes, ears, nose, 
throat, neck, and lymph nodes. At subsequent visits, physical examination includes as a 
minimum the examination of general appearance, heart, and peripheral vascular 
assessment. 
Other examinations will be performed if indicated, based on medical history and/or 
symptoms. 
Information for all physical examinations must be included in the source documentation at 
the study site.  
The physical examination will be reported in the eCRF as either normal or abnormal; in 
the latter case, the investigator should specify whether it is clinically relevant. Clinically 
relevant physical abnormalities present at the time of signing off the ICF must be reported 
on the medical history form of the eCRF. Physical examination findings, which meet the 
definition of an AE [Section 9.1.1] and are made after signing off the ICF, must be recorded 
on the AE form of the eCRF. 
7.2.3.3 Weight and height 
Height will be measured without shoes at Screening only.  
Body weight must be carefully monitored during the study since it is one of the safety 
endpoints. Body weight must be measured at all visits in a standardized way, as follows: 
subjects should always be weighed under similar conditions, e.g., same scale, similar 
clothing (i.e., underwear only), and similar interval between weighing and last meal. The 
investigator will be asked to indicate on the body weight form in the eCRF whether an 
increase in body weight from the previous visit is judged to be clinically relevant and 
whether it could be a sign of fluid retention. In addition, subjects will be instructed to 


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monitor their body weight at home on a weekly basis and to contact the study site if they 
notice an unusual weight increase since the start of the study.  
Body weight and height data measured at site will be recorded in the eCRF. 
7.2.3.4 ECG assessment 
ECGs will be performed with the subject in a fully rested supine position after the subject 
has been allowed to rest for a minimum of 5 minutes prior to the measurement. 
The following variables will be evaluated: HR (bpm), PR (ms), QRS (ms), QT (ms), QTc 
(ms), and any ECG findings. QTc (ms) will be calculated according to Bazett’s and 
Fridericia’s formula (QTcB = QT/(RR) ½ and QTcF = QT/(RR) ⅓, respectively).  
Digital 12-lead ECG devices will be provided to each site by the central ECG vendor for 
the duration of the study. The central ECG vendor will be used for the evaluation of all 
protocol-mandated ECGs, including re-tests due to ECG abnormalities and ECGs 
performed at unscheduled visits. The site personnel will electronically transmit the ECGs 
to the central ECG vendor for central reading. The reports from the central ECG laboratory 
will be sent to the site within a few days.  
All ECG reports must be reviewed, signed and dated by the investigator/delegate within 
10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the ECG report whether abnormal values or findings 
are considered clinically relevant or not. Clinically relevant ECG findings that are known 
at the time of signing of the ICF must be recorded in the medical history form of the eCRF. 
Any clinically relevant ECG abnormalities detected after signing of ICF must be reported 
as an AE or SAE as appropriate [see Sections 9.1.1, 9.1.2], and must be followed until the 
value returns to within the normal range or is stable, or until the change is no longer 
clinically relevant. 
Details on ECG procedure (recording, transfer of data and reporting to the site) will be 
provided in the ECG manual.  
7.2.3.5 Laboratory assessments 
7.2.3.5.1 Type of laboratory 
A central laboratory or designated laboratory (see laboratory manual for contact details) 
will be used for all protocol-mandated laboratory tests (except PK and urine pregnancy 
tests), including re-tests due to laboratory abnormalities and laboratory tests performed at 
unscheduled visits. 
At the end of the RI period (Day –1), two samples will be drawn: 

One sample for central laboratory, and


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
One sample for local laboratory: to measure hemoglobin, creatinine (to determine
eGFR), AST/ALT and pregnancy test for women of childbearing potential to confirm
eligibility of subject for randomization. Decision on eligibility and randomization will
be based on local laboratory results. These local laboratory results (with the
corresponding normal ranges) must be recorded in the eCRF.
For other exceptional circumstances (e.g., subject is hospitalized in a different hospital 
from the study center due to a medical emergency, or missing central laboratory results 
from a scheduled or unscheduled visit), local laboratory results of the parameters described 
in Section 7.2.3.5.2 with the corresponding normal ranges will be entered into the clinical 
database via dedicated eCRF forms.  
If two or more consecutive central laboratory samples are lost or cannot be analyzed for 
whatever reason, the investigator can collect an additional sample as soon as possible for 
repeat analysis, unless a local laboratory sample was collected within the same 
time-window and these test results are available (in which case they must be recorded in 
the eCRF). 
Laboratory reports will be provided by the central laboratory to the investigator/delegate. 
All laboratory reports must be reviewed, signed and dated by the investigator/delegate 
within 10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 
considered clinically relevant or not. Clinically relevant laboratory findings that are known 
at the time of signing of ICF must be recorded in the medical history form of the eCRF. 
Any clinically relevant laboratory abnormalities detected after signing of the ICF must be 
reported as an AE or SAE as appropriate [see Sections 9.1.1 and 9.1.2], and must be 
followed until the value returns to within the normal range or is stable, or until the change 
is no longer clinically relevant. 
In the event of specific (pre-defined) laboratory abnormalities, the central laboratory will 
alert the sponsor and the site personnel. Alert flags that will trigger such notifications are 
displayed in the laboratory guidelines. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.2.3.5.2 Blood tests 
The amount of blood collected from an individual subject per visit will be described in the 
laboratory manual.  


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Hematology 

Hemoglobin

Hematocrit

Erythrocyte count

Reticulocyte count

Leukocyte count with differential counts

Platelet count

MCV, as part of a standard complete blood count, is used along with other red blood
count indices (MCH and MCHC)
Blood chemistry 

ALT, AST, Alkaline phosphatase

Total and direct bilirubin

Cholesterol, triglyceride, high density lipoprotein, low density lipoprotein

Creatinine, creatine kinase

eGFR (estimated using the CKD-EPI creatinine equation Levey 2009)

Uric acid

Albumin, Protein total

Glucose

Sodium, potassium

NT-proBNP [see Section 7.2.5]
7.2.3.5.3 Urinalysis
Urine samples will be collected at each visit at trough before taking the study treatment 
and the standardized background antihypertensive therapy according to Table 2 and 
Table 3. The collected urine will be transferred into a standard urine collection tube for 
shipment to central laboratory. Details about the collection, sampling, storage, shipment 
procedures, transfer and reporting of results can be found in the laboratory manual. 
7.2.3.5.3.1 UACR determination 
A midstream, clean-catch urine specimen will be collected for the determination of UACR 
(mg/g).  


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7.2.3.5.3.2 Study treatment adherence 
Urine samples will be analyzed by a designated central laboratory for the presence of 
valsartan (one of the components of the standardized background antihypertensive 
therapy).  
7.2.3.5.4 Pregnancy tests 
Serum pregnancy tests for women of childbearing potential will be performed during the 
study according to Table 3. Serum pregnancy tests will be sent to the central lab for analysis 
and the result will be sent to the investigator/delegate (see laboratory manual for details on 
collection, sampling, storage, shipment procedures, and reporting of results). Reporting 
procedures of pregnancy are described in Section 9.4.1. 
During the SB aprocitentan part urine pregnancy tests will be performed between 
scheduled visits (i.e., monthly) with approved kits provided by the site to subject at home 
[see Table 3]. If pregnancy is suspected, the subject must immediately contact the site and 
a serum pregnancy test must be performed immediately at the site. The urine kit will be 
provided by the central laboratory to sites. The results of the urine pregnancy tests will not 
be collected in the eCRF.  
Reporting procedures for pregnancy are described in Section 9.4.1. 
7.2.4 Pharmacokinetic assessments 
Pre-dose (i.e., trough) blood samples for determination of PK will be collected for all 
subjects to provide information about the concentration of aprocitentan in the target 
population. Blood samples will be drawn at trough (before dose of study treatment and the 
standardized background antihypertensive therapy) as defined in Section 7.2.4. 
7.2.4.1 Sampling, labeling, storage and shipment 
The date and exact actual clock time of collection of each blood sample, as well as the 
exact dates and time of the study treatment administration (including the background 
therapy of CCB, ARB and diuretic) prior to and after blood draw, will be entered in the 
eCRF. 
Details about the collection, sampling, storage, and shipment procedures can be found in 
the laboratory manual. Sites will receive required material from the central laboratory 
before the start of the study (e.g., tubes, labels, shipment materials). The site personnel will 
take care of the shipment of the plasma samples to central laboratory who will forward the 
PK samples to the Idorsia bioanalytical laboratory at time intervals agreed with the sponsor. 
7.2.4.2 Bioanalysis 
The analysis of aprocitentan in plasma will be performed using a validated liquid 
chromatography coupled to tandem mass spectrometry assay. The foreseen limit of 


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quantification is 5 ng/mL. The analysis will be performed by the Idorsia bioanalytical 
laboratory.  
The PK analysis will be performed in a time interval which is covered by plasma stability. 
The results will not be transferred to the study team until data base lock. 
The samples will be destroyed upon signature of the Clinical Study Report (CSR). 
7.2.5 Biomarker assessments 
At Screening, end of RI (Day –1) and at the end of the DB part 1 (Week 4), plasma/serum 
samples will be collected for all subjects (if allowed per local/regulatory guidelines) to 
explore biomarkers that reflect the ET system activity. Such biomarkers may include, but 
are not limited to, CT-proET-1, ET-1, ET-3, renin and aldosterone for ET system activity. 
These assessments will provide information whether RHT is an ET-1 driven form of 
hypertension, whether these biomarkers can be used to characterize the study population, 
and whether these biomarkers are impacted by study treatment. 
In addition, the following biomarkers will be evaluated at the end of RI (Day –1), at the 
end of DB part 1 (Week 4), during SB aprocitentan part 2 (Week 20 and Week 36) and 
during DB-WD part 3 (Week 40) to explore whether aprocitentan has an effect on 
micro- and macrovascular complications (e.g., edema, heart overload): Such biomarkers 
may include, but are not limited to, NT-proBNP MR-proANP, and Troponin I. In addition 
to these time points NT-proBNP will also be measured at Screening (Visit 1), Visit 7 
(Week 6), Visit 8 (Week 12), Visit 10 (Week 28), Visit 14 (Week 44), Visit 15/EOT 
(Week 48), and Visit 16/EOS (EOT plus 30 days) as part of central laboratory assessments. 
Samples will be measured by a designated central laboratory at frequencies defined by the 
stability of the samples. Details about the collection, sampling, storage and shipment 
procedures can be found in the laboratory manual. If consented by the subject, the collected 
biomarker samples will be stored in the sponsor´s research repository, which may be used 
for future research on the endothelin system activity. The stored samples will be destroyed 
within 18 months after the completion of the study. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol  
For an individual subject, the study is completed as per protocol when the 48-week 
randomized treatment period and the 30-day safety FU period have been completed. 
8.2 Premature withdrawal from study  
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 


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participation in all components of the study (i.e., WD 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 WD 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. WD from 
the study may also result from a decision by the sponsor for any reason, including 
premature termination or suspension of the study [see Section 8.3]. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual have failed. The site must take preventive measures to 
avoid a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted in the event the 
subject cannot be reached). If the subject cannot be reached, the site must make a 
reasonable effort to contact the subject, document all attempts (date, time and type of 
contact made), and enter the loss of follow-up information into the eCRF. The following 
methods must be used: at least three attempts at contacts (e.g., telephone calls, or e-mails) 
must be placed to the last available telephone number or e-mail address, and one registered 
letter must be sent by post to the last available home address. Additional methods may be 
acceptable if they are compliant with local rules/regulations (e.g., a visit by site personnel 
to the subject’s home), respecting the subject’s right to privacy. If the subject is still 
unreachable after all contact attempts listed above he/she will be considered to be lost to 
follow-up. 
The reason for premature WD from the study must be recorded in the eCRF. 
If for whatever reason (except death or loss-to-follow-up) a subject is withdrawn from the 
study, the investigator should make his/her 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, as 
described in Section 8.4. 
8.3 Premature termination or suspension of the study 
The sponsor reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If a study is prematurely suspended or terminated, the sponsor will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons 
for the suspension or termination. 


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If the study is suspended or prematurely terminated for any reason, the investigator — in 
agreement with the sponsor — must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. The sponsor may inform 
the investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates a study without prior agreement from 
the sponsor, the investigator must promptly inform the sponsor personnel and the IEC/IRB, 
and provide both with a detailed written explanation of the termination or suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of a study, the 
investigator must promptly notify the sponsor personnel and provide a detailed written 
explanation of the termination or suspension. 
Any suspension or premature termination of the study must be discussed with the IDMC. 
8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature WD from the study, whichever applies, 
the investigator/delegate will explain to subjects what treatment(s) / medical care is 
necessary and available according to local regulations. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Safety definitions 
9.1.1 Definition of adverse events  
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A treatment-emergent AE is any AE temporally associated with the use of study treatment 
(from study treatment initiation until 30 days after study treatment discontinuation), 
whether or not considered by the investigator as related to study treatment. 
AEs include: 

Exacerbation of a pre-existing disease.

Increase in frequency or intensity of a pre-existing episodic disease or medical
condition.

Disease or medical condition detected or diagnosed during the course of the study even
though it may have been present prior to the start of the study.

Continuous persistent disease or symptoms present at study start that worsen following
the start of the study (i.e., signing of informed consent).


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
Abnormal assessments (e.g., change on physical examination, ECG findings), if they
represent a clinically significant finding that was not present at study start or worsened
during the course of the study.

Laboratory test abnormalities if they represent a clinically significant finding,
symptomatic or not, which was not present at study start or worsened during the course
of the study or led to dose reduction, interruption or permanent discontinuation of
study treatment.
9.1.2 Definition of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following 
criteria: 

Fatal.

Life-threatening: Refers to an event in which the subject was at risk of death at the
time of the event. It does not refer to an event that hypothetically might have caused
death had it been more severe.

Requiring in-patient hospitalization or prolongation of existing hospitalization.

Resulting in persistent or significant disability or incapacity.

Congenital anomaly or birth defect.

Medically significant: Refers to important medical events that may not immediately
result in death, be life-threatening, or require hospitalization but may be considered to
be SAEs when, based upon appropriate medical judgment, they may jeopardize the
subject, and may require medical or surgical intervention to prevent one of the
outcomes listed in the definitions above.
The following reasons for hospitalization are not considered as SAEs: 

Hospitalization for cosmetic elective surgery, or social and/or convenience reasons

Hospitalization for pre-planned (i.e., planned prior to signing ICF) surgery or standard
monitoring of a pre-existing disease or medical condition that did not worsen, e.g.,
hospitalization for coronary angiography in a subject with stable angina pectoris
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
9.1.3 Definition of suspected unexpected serious adverse reaction 
The expectedness of an adverse reaction is determined by the sponsor in the reference 
safety information (RSI) section provided in the most recent version of the IB. Any SAE 
that is assessed as related and unexpected against the RSI is defined as a SUSAR. 


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9.1.4 Definition of the intensity of adverse events 
The intensity of AEs is graded on a three-point scale — mild, moderate, severe — as 
follows: 

Mild
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 

Moderate
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 

Severe
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
These terms are used to describe the intensity of a specific event. Medical judgment should 
be used on a case-by-case basis. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.1.2]. Seriousness, 
rather than intensity assessment, determines the regulatory reporting obligations see 
Section 9.3.2. 
9.1.5 Relationship to study treatment 
Each AE/SAE 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. 
9.1.6 Relationship to study design or protocol-mandated procedure  
An AE/SAE is defined as related to study design or protocol-mandated procedure if it 
appears to have a reasonable possibility of a causal relationship to either the study design 
or to a protocol-mandated procedure (e.g., discontinuation of a subject’s previous treatment 
leading to exacerbation of underlying disease). The determination of the likelihood that the 
study design / a protocol-mandated procedure caused the AE/SAE will be provided by the 
investigator. 
9.2 Time period and frequency for AE/SAE assessment and follow-up 
The occurrence of an AE/SAE may come to the attention of study personnel during study 
visits, phone calls and interviews of study participant presenting for medical care. At each 


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study visit (scheduled or unscheduled), the investigator will inquire about the occurrence 
of AE/SAEs since the last visit. 
The clinical course of AEs/SAEs will be followed according to local standard medical 
practices. 
9.2.1 Follow-up of adverse events  
AEs still ongoing at the EOS must be followed up until they are no longer considered 
clinically relevant or until stabilization.  
9.2.2 Follow-up of serious adverse events 
SAEs still ongoing at the EOS visit must be followed up until resolution or stabilization, 
or until the event outcome is provided.  
9.3 Reporting procedures 
9.3.1 Reporting of adverse events 
All AEs with an onset date after signing of the ICF and up to 30 days after study treatment 
discontinuation must be recorded on specific AE forms of the eCRF.  
Information to be collected on an AE form in the eCRF includes date of onset, action taken 
with the study treatment, outcome of AE, date of resolution (if applicable), as well as PI’s 
assessment of intensity and relationship to study treatment, standardized background 
antihypertensive therapy, study design or protocol mandated procedures. 
If the intensity of an AE worsens during the study, a new AE should be reported in the 
eCRF with the higher intensity. If the intensity of an AE lessens during the study, no change 
in the intensity is required to be reported.  
Follow-up information on ongoing AE obtained after the subject’s EOS visit will not be 
collected in the eCRF. 
9.3.2 Additional reporting procedures for serious adverse events 
All SAEs must be reported by the investigator to the sponsor’s Global Drug Safety 
department within 24 hours of the investigator’s first knowledge of the event. 
All SAEs occurring after signing of the ICF up to 30 days after study treatment 
discontinuation must be recorded on an SAE form, regardless of the investigator-attributed 
causal relationship with study treatment or study-mandated procedures. 
The SAE forms must be sent to the sponsor’s Global Drug Safety department (see contact 
details on the SAE form). The investigator must complete the SAE form in English, and 
must assess the event’s causal relationship to the study treatment. 


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Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The sponsor’s Global Drug Safety personnel may contact the 
investigator to obtain further information. 
If the subject is hospitalized in a hospital other than that of the study site, it is the 
investigator’s responsibility to contact this hospital to obtain all SAE-relevant information 
and documentation. 
Follow-up information on an ongoing SAE obtained after a subject’s EOS visit must be 
reported to the sponsor’s Global Drug Safety department, but is not recorded in the eCRF. 
New SAEs occurring after the 30-day FU period must be reported to the sponsor’s Global 
Drug Safety department within 24 hours of the investigator’s knowledge of the event, only 
if considered by the investigator to be causally related to previous exposure to the study 
treatment. 
9.3.3 Additional reporting procedures for SUSAR 
The sponsor will report any SUSAR see definition in Section 9.1.3 to concerned health 
authorities (including the EudraVigilance database if the study is conducted in Europe), 
IECs/IRBs and investigators. 
9.4 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued [see Section 5.1.11. The investigator must counsel the subject and discuss 
the risks of continuing with the pregnancy and the possible effects on the fetus. 
9.4.1 Reporting of pregnancy 
Any pregnancy occurring in a female subject after signing of the ICF and up to 30 days 
after study treatment discontinuation must be reported to the sponsor’s Global Drug Safety 
department within 24 hours of the investigator’s knowledge of the event. 
Pregnancies must be reported on the sponsor Pregnancy form, which is faxed to the 
sponsor’s Global Drug Safety department (see contact details provided on the Pregnancy 
form). 
The investigator must complete the pregnancy form in English. 
9.4.2 Follow-up of pregnancy 
Any pregnancies must be followed-up to their conclusion and the outcome must be reported 
to the sponsor’s Global Drug Safety department.  


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Any AE associated with the pregnancy occurring up to the EOS visit must be reported on 
separate AE forms in the eCRF. Any SAE occurring during the pregnancy must be reported 
on an SAE form as described in Section 9.3.2. 
9.5 Reporting of study treatment overdose, misuse, and abuse  
Study treatment overdose, misuse, and abuse will be reported as an AE only if associated 
with signs or symptoms.  
Overdose: Administration of a dose (per intake or cumulatively) which is above the 
instructions provided in the protocol. When applying this definition, clinical judgment 
should always be applied (e.g., just because a subject took two tablets instead of one it is 
not “overdose” as per definition). 
Misuse: Intentional and inappropriate use which is different from the instructions provided 
in the protocol. 
Abuse: Intentional excessive use with harmful physical or psychological effects. 
9.6 Study safety monitoring 
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific examinations as required) is monitored and reviewed on a continuous basis 
by the sponsor (in charge of ensuring subjects’ safety as well as data quality) by 
periodically monitoring clinical studies activities from protocol conception to database 
closure.  
In addition, an IDMC is monitoring safety data on a study level [see Section 3.3.2]. 
10 STATISTICAL METHODS 
10.1 Analysis sets 
10.1.1 Screened Set 
The Screened Set (SCR) includes all subjects who have given informed consent to 
participate in the study and have a subject number. 
10.1.2 Run-in Set 
The Run-in Set (RIS) includes all subjects from the SCR who received at least one dose of 
SB placebo in the RI period.  
10.1.3 Full Analysis Set (FAS) 
The FAS includes all subjects who were randomized and have a baseline SiSBP, measured 
by AOBPM. In order to adhere to the intent-to-treat principle as much as possible, subjects 
will be evaluated according to their assigned study treatment in the DB part: aprocitentan 
25 mg, aprocitentan 12.5 mg or placebo. 


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10.1.4 Per Protocol Set 
The PPS includes all subjects from the FAS without a major protocol deviation (to be 
defined in the SAP).  
10.1.5 Modified FAS 
The modified FAS (mFAS) includes all subjects in the FAS who were re-randomized in 
the DB-WD part of the study and who have a Week 36 SiSBP, measured by AOBPM. 
Subjects will be evaluated according to their assigned study treatment in the DB-WD part: 
aprocitentan 25 mg or placebo. 
10.1.6 ABPM FAS 
The ABPM FAS (aFAS) includes all subjects from the FAS who have a baseline 24 h mean 
SBP, measured by ABPM. Subjects will be evaluated according to their assigned study 
treatment in the DB part. 
10.1.7 Modified ABPM FAS 
The modified ABPM FAS (maFAS) includes all subjects from the aFAS who were 
re-randomized in the DB-WD part of the study and who have a Week 36 24 h mean SBP, 
measured by ABPM. Subjects will be evaluated according to their assigned study treatment 
in the DB-WD part. 
10.1.8 Safety Analysis Set 
The Safety Analysis Set (SAF) includes all randomized subjects who received at least one 
dose of study treatment in the DB part. Subjects will be evaluated according to the study 
treatment they received in the DB part. 
10.1.9 Modified Safety Analysis Set 
The modified SAF (mSAF) includes subjects from the SAF received at least one dose of 
study treatment in the DB-WD part. Subjects will be evaluated according to the study 
treatment they received in the DB-WD part.  
10.1.10 
Pharmacokinetic Set 
The PK set includes all subjects from the FAS with at least one valid PK assessment and 
no major protocol deviation pertaining to PK (to be defined in the SAP). 
10.1.11 
Usage of the analysis sets 
The role of the analysis sets in each of the study parts (DB, SB aprocitentan and DB-WD) 
is summarized in Table 4. 


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Table 4 
Role of the analysis sets 
ABPM = ambulatory blood pressure monitoring; aFAS = ABPM Full Analysis Set; AOBPM = automated office blood 
pressure measurement; DB = double-bind; FAS = Full Analysis Set; maFAS= modified ABPM Full Analysis Set; mFAS 
= modified Full Analysis Set; mSAF = modified Safety Analysis Set; PK = pharmacokinetic(s); PPS = Per Protocol Set; 
SAF = Safety Analysis Set; SB = single-blind; WD = withdrawal. 
The SCR and RIS will be used for subject listings. 
10.2 Variables 
10.2.1 Primary efficacy variable 
Refer to Section 6.1.1. 
10.2.2 Secondary efficacy variables 
Refer to Section 6.1.2. Details for the derivation of ABPM-based endpoints are given 
below. The criteria for ABPM readings to be evaluable for analysis will be listed in the 
SAP. 

Changes from baseline to Week 4 of DB treatment in 24 h mean SBP and DBP
measured by ABPM. At each visit the 24 h mean SBP (DBP) is derived from the area
under the SBP (DBP)-time curve, divided by the time span. The area under the curve
is calculated by the trapezoidal rule. Time points later than 25 hours after the first time
point will be excluded from the calculation. The change from baseline to Week 4 will
be obtained by subtraction.

Changes from Week 36 to Week 40 of DB-WD treatment in 24 h mean SBP and DBP
measured by ABPM. These are derived similarly to changes from baseline to Week 4
of DB treatment in 24 h mean SBP and DBP, with baseline and Week 4 replaced by
Week 36 and Week 40, respectively.
10.2.3 Safety variables 
Refer to Section 6.2.  
Study Part 
DB 
SB 
DB-WD 
Efficacy endpoints based on AOBPM 
FAS (PPS) 
- 
mFAS 
Efficacy endpoints based on ABPM 
aFAS 
- 
maFAS 
Safety endpoints 
SAF 
SAF 
mSAF 
PK endpoints 
PK 
-
- 


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10.3 Description of statistical analyses 
10.3.1 Overall testing strategy 
Three null hypotheses will be tested in this study. The first two hypotheses (H10 and H20) 
will be tested in parallel using the Bonferroni correction. The third hypothesis (H30) will 
only be tested if H10 or H20 is rejected. 
The first null hypothesis H10 is that there is no difference between aprocitentan 25 mg and 
placebo in the DB part in the mean change from baseline to Week 4 in mean trough SiSBP. 
The alternative hypothesis H1a is that there is a difference between these groups: 
H10: μ1 = μ0 vs H1a: μ1 ≠ μ0. 
Here μ0 and μ1 denote the mean change from baseline to Week 4 in mean trough SiSBP in 
the placebo and aprocitentan 25 mg group, respectively. This hypothesis will be tested at a 
two-sided significance level of 0.025. 
The second null hypothesis H20 is that there is no difference between aprocitentan 12.5 mg 
and placebo in the DB part in the mean change from baseline to Week 4 in mean trough 
SiSBP. The alternative hypothesis H2a is that there is a difference between these groups: 
H20: μ2 = μ0 vs H2a: μ2 ≠ μ0. 
Here μ0 and μ2 denote the mean change from baseline to Week 4 in mean trough SiSBP in 
the placebo and aprocitentan 12.5 mg group, respectively. This hypothesis will be tested at 
a two-sided significance level of 0.025. 
The third null hypothesis H30 is that there is no difference between aprocitentan 25 mg and 
placebo in the DB-WD part in the mean change from Week 36 to Week 40 in mean trough 
SiSBP. The alternative hypothesis H2a is that there is a difference between these groups: 
H30: ν1 = ν0 vs H3a: ν1 ≠ ν0. 
Here ν0 and ν1 denote the mean change from Week 36 to Week 40 in mean trough SiSBP 
in the placebo and aprocitentan 25 mg group, respectively. This hypothesis will only be 
tested if H10 or H20 is rejected: at a two-sided significance level of 0.05 if both H10 and H20 
have been rejected and at a two-sided significance level of 0.025 if only one of the H10 and 
H20 has been rejected. This way the overall type I error is protected at 0.05. 
10.3.2 Analysis of the primary efficacy variable 
The main analysis of the change from baseline to Week 4 in mean trough SiSBP measured 
by AOBPM will be conducted on the FAS. The treatment groups in this analysis are 
aprocitentan 25 mg, aprocitentan 12.5 mg and placebo. The first and second null 
hypotheses (H10 and H20) will be tested as described in Section 10.3.1.  


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10.3.2.1 Main analysis in the DB part 
AOBPM measurements obtained after premature discontinuation of DB treatment will be 
excluded from this analysis (i.e., considered as missing), leading to a hypothetical strategy 
estimand in the terminology of [ICH E9 (R1)]. This approach was chosen because it is 
anticipated that the effect of a treatment on BP will be lost soon after the treatment has 
been discontinued. In this setting, it is not the usual practice to assess effectiveness after 
(premature) treatment discontinuation [O’Neill 2012]. 
Changes from baseline to post-baseline visits up to Week 4 in mean trough SiSBP will be 
analyzed using a mixed model with factors for treatment group, time and treatment by time 
interaction and covariates for baseline SiSBP and the interaction between baseline and 
time. An unstructured covariance matrix will be used to account for the correlation between 
repeated measurements from the same subject. 
Least Squares Mean (LSM) differences vs placebo at Week 4 and their 97.5% CIs will be 
obtained from the model. The associated P-values will be used to test the first and second 
null hypotheses.  
10.3.2.2 Handling of missing data in the DB part 
Based on the Phase 2 study, AC-080A201, it is expected that 5% of subjects will have a 
missing Week 4 AOBPM. Missing data will not be imputed but will be handled by the 
mixed model assuming that the data are missing at random (MAR).  
10.3.2.3 Sensitivity analyses for missing data in the DB part 
The impact of deviations from the MAR assumption underlying the mixed model will be 
investigated in sensitivity analyses assuming that in the aprocitentan groups the data are 
missing not at random (MNAR) [Mallinckrodt 2013].  
Multiple imputation analyses will be performed assuming a monotone missing data pattern 
(i.e., if data are missing at a given visit, they are also missing at subsequent visits). Any 
non-monotone missing data will first be imputed under MAR, which is considered 
reasonable because the proportion of non-monotone missing data (i.e., AOBPM missing at 
Week 2, but observed at Week 4) is expected to be low. 
Two control-based multiple imputation analyses will be performed under MNAR: 
a Jump to Reference (J2R) and a Copy Reference (CR) approach [Carpenter 2013]. 
In these approaches, multiple imputation of missing values will be performed based 
on the assumption that subjects with missing data in the aprocitentan arms follow 
the trajectory of the placebo arm, conditional on subjects’ data available prior to 
discontinuation (baseline SiSBP for the J2R approach; baseline as well as available 
post-baseline SiSBP for the CR approach). Imputation is performed sequentially, 
one visit at a time [Ratitch 2013]. At each visit a regression model is fitted using 


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data from the placebo arm only, so missing data in the aprocitentan arms are 
imputed based on the predicted outcome in the placebo arm. The resulting multiple 
data sets are subsequently analyzed using the same mixed model as for the main 
analysis Results from these analyses are combined using Rubin’s methodology 
[Rubin 1987].  
In addition, a tipping point approach will be used to assess how severe departures from the 
MAR assumption must be to overturn the conclusions of the main analysis. Further details 
of the sensitivity analyses are given in the SAP. 
10.3.2.4 Supportive analyses in the DB part 
In a supportive analysis, all AOBPM measurements obtained after premature 
discontinuation of DB treatment will be included in the analysis, leading to a treatment 
policy strategy estimand in the terminology of [ICH E9 (R1)]. 
10.3.2.5 Subgroup analyses in the DB part 
The aim of the subgroup analyses is to explore the consistency of treatment effect in 
relevant subgroups: 

Age (< 65 years vs ≥ 65 years),

Sex (male/female),

Race (Black, Caucasian, Other),

Region (to be defined in the SAP),

UACR at randomization visit (< 30 mg/g, 30–300 mg/g, > 300 mg/g),
Results of the subgroup analyses will be displayed in a forest plot and will include:

An estimate of the treatment effect for each aprocitentan dose vs placebo with its 95%
CI for each level of the subgroup. It will be calculated as the LSM difference vs
placebo at Week 4 obtained separately for each subgroup level as described for the
main analysis [Section 10.3.2.1].

A p-value for the interaction test obtained from the mixed model for the main analysis
extended with factors for the subgroup and treatment by subgroup interaction.

A vertical reference line displayed at the level of the overall treatment effect.
The study is not designed or powered to detect interactions but an arbitrary two-sided 
significance level of 0.10 will be used for the interpretation of the interaction test. No 
multiplicity adjustment is applied as these subgroup analyses are exploratory in nature. 
10.3.3 Analysis of the key secondary efficacy variable 
The main analysis for the change from Week 36 to Week 40 in mean trough SiSBP 
measured by AOBPM will be conducted on the mFAS. The treatment groups in this 


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analysis are aprocitentan 25 mg and placebo. The analyses will be adjusted for the stratum 
in the re-randomization (i.e., randomized treatment in the DB part). The third null 
hypothesis (H30) will be tested as described in Section 10.3.1.  
10.3.3.1 Main analysis in the DB-WD part 
For the main analysis in the DB-WD part the same approach was chosen as for the DB part 
for the reasons given in Section 10.3.2.1. In addition, the initiation of antihypertensive 
rescue medication (which is allowed in this part of the study) could influence the BP of a 
subject [O’Neill 2012]. For this reason, AOBPM measurements obtained after premature 
discontinuation of DB-WD treatment or initiation of antihypertensive rescue medication in 
the DB-WD part will be excluded from this analysis (i.e., considered as missing), leading 
to a hypothetical strategy estimand in the terminology of [ICH E9 (R1)]. 
Changes from Week 36 to visits up to Week 48 in mean trough SiSBP will be analyzed 
using a mixed model with factors for stratum, treatment group, time, and treatment by time 
interaction, covariates for Week 36 SiSBP and the interaction between Week 36 and time 
and an unstructured covariance matrix. 
LSM differences vs placebo for the change from Week 36 to Week 40 and their 95% CIs 
will be obtained from the model. The associated P-values will be used to test the third null 
hypothesis. LSM differences and their 95% CIs for changes from Week 36 to Weeks 44 
and 48 will be obtained from the same model. 
10.3.3.2 Handling of missing data in the DB-WD part 
It is expected that 10% of subjects in the mFAS will have a missing Week 40 AOBPM. 
Missing data will not be imputed but will be handled by the mixed model assuming that 
the missing data are MAR. 
10.3.3.3 Sensitivity analyses for missing data in the DB-WD part 
The impact of deviations from the MAR assumption underlying the mixed model will be 
investigated in sensitivity analyses under MNAR as described for the DB part 
[Section 10.3.2.3]. 
10.3.3.4 Supportive analyses in the DB-WD part 
In a supportive analysis, all AOBPM measurements obtained after premature 
discontinuation of DB-WD treatment or initiation of antihypertensive rescue medication in 
the DB-WD part will be included in the analysis, leading to a treatment policy strategy 
estimand in the terminology of [ICH E9 (R1)]. Additionally, an Analysis of Covariance 
(ANCOVA) will be performed for the change from Week 36 to Week 40 imputing missing 
data using last observation carried forward. 


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10.3.3.5 Subgroup analyses in the DB-WD part 
Sub-group analyses in the DB-WD part will be performed as described for the DB part 
[Section 10.3.2.5]. In addition, subgroups based on the initiation of antihypertensive rescue 
medication prior to the DB-WD part (Y/N) will be considered. Subjects without 
antihypertensive rescue medication are considered an enriched sub-population of the 
mFAS. 
10.3.4 Analysis of the other secondary efficacy variables 
All other secondary efficacy variables will be tested at the two-sided significance level 
of 0.05. 

Change from baseline to Week 4 of DB treatment in mean trough SiDBP measured
by AOBPM will be analyzed in the FAS using the same model as specified for SiSBP
(main analysis) in the DB part.

Changes from baseline to Week 4 of DB treatment in 24 h mean SBP and DBP
measured by ABPM will be analyzed in the aFAS using an ANCOVA with a factor
for treatment group and a covariate for baseline 24 h mean SBP (or DBP).

Change from Week 36 to Week 40 of DB-WD treatment in mean trough SiDBP as
measured by AOBPM will be analyzed in the mFAS using the same model as
specified for SiSBP (main analysis) in the DB-WD part.

Changes from Week 36 to Week 40 of DB-WD treatment in 24 h mean SBP and DBP
as measured by ABPM will be analyzed in the maFAS using the same ANCOVA as
described for changes from baseline to Week 4 of DB treatment in 24 h mean SBP
and DBP, but with baseline replaced by Week 36.
10.3.5 Analysis of other efficacy variables 
The analyses of other efficacy variables will be described in detail in the SAP. 
10.3.6 Analysis of the safety variables  
Safety analyses in the DB and SB aprocitentan parts will be performed on the SAF. Safety 
analyses in the DB-WD part will be performed on the mSAF.  
Only treatment-emergent safety data up to EOT + 30 days will be considered in tables and 
figures. All safety data will be included in listings based on the SCR or RI (as appropriate), 
with flags for safety data not considered to be treatment-emergent.  
10.3.6.1 Adverse events 
10.3.6.1.1 Treatment-emergent AEs 
Treatment-emergent AEs will be tabulated by study part (DB, SB or DB-WD), treatment 
group (within study part), system organ class (SOC) and preferred terms within each SOC: 
the number and percentage of subjects who experienced at least one AE, at least one AE 


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within each SOC and at least one AE within each preferred term will be displayed. AEs 
will also be summarized by decreasing frequency of preferred term. AEs will also be 
tabulated by maximum intensity and relationship to aprocitentan or placebo. If an AE starts 
in one study part and ends in the next part without increasing intensity, it is counted only 
in the first part. If, however, the intensity of the AE increases in the second part it is counted 
in that part as well. 
10.3.6.1.2 Treatment-emergent SAEs 
SAEs will be summarized in a similar manner as described in Section 10.3.6.1.1. 
10.3.6.1.3 AEs leading to premature discontinuation of study treatment 
(S)AEs leading to premature discontinuation of study treatment will be summarized in a
similar manner as described in Section 10.3.6.1.1.
10.3.6.2 Laboratory data 
10.3.6.2.1 Changes from baseline and Week 36 in laboratory variables 
Changes from baseline for laboratory tests to visits in the DB and SB parts (henceforth, 
DB+SB) will be summarized using descriptive statistics by visit and treatment group (in 
the DB part). Changes from Week 36 to visits in the DB-WD part will be summarized by 
visit and treatment group (in the DB-WD part). Data will be displayed in SI units whenever 
possible and graphical approaches will be applied for certain variables.  
10.3.6.2.2 Treatment-emergent marked laboratory abnormalities 
The number (%) of subjects with laboratory abnormalities will be tabulated by study part 
(DB+SB and DB-WD) and treatment group (within study part). Laboratory abnormalities 
will be defined in the SAP. 
10.3.6.2.3 Ratios to baseline and Week 36 of NT-proBNP 
Ratios to baseline of NT-proBNP will be log transformed (base e) and analyzed in the 
DB+SB parts using a mixed model for repeated measurements with factors for treatment 
group (in the DB part), visit (up to Week 36) and treatment by visit interaction and 
covariates for baseline log (NT-proBNP) and treatment by baseline interaction. Ratios to 
Week 36 of NT-proBNP in the DB-WD part will be analyzed similarly, but with baseline 
replaced by Week 36. 
10.3.6.3 Vital signs 
Descriptive statistics by study part (DB+SB or DB-WD), visit and treatment group (within 
study part) will be provided for observed treatment-emergent values and absolute changes 
from baseline and Week 36 in body weight and pulse rate.  


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10.3.6.4 ECG 
Descriptive statistics by study part (DB+SB or DB-WD), visit and treatment group (within 
study part) will be provided for observed treatment-emergent values and absolute changes 
from baseline in numeric 12-lead ECG values (HR, PR, QRS, QT, QTcB, and QTcF).  
Treatment-emergent marked abnormalities for selected 12-lead ECG variables (HR, PR, 
QT, QTcB, and QTcF) will be summarized by study part and treatment group. 
In addition, summaries of treatment-emergent morphological ECG abnormalities that were 
not present before first study treatment intake (using data from the ECG provider) will be 
provided.  
10.3.6.5 Treatment-emergent MACE and MACE-plus 
The number (%) of subjects with MACE and MACE-plus will be tabulated by study part 
(DB, SB or DB-WD) and treatment group (within study part). Time from Randomization 
to (first) MACE will also be described using a Cox model with a time-dependent covariate 
for treatment. Times to event will be censored at EOT + 30 days. MACE-plus will be 
analyzed similarly. 
10.3.6.6 Increase in dose of existing diuretic or addition of new diuretic due to fluid 
retention 
This endpoint will be analyzed similarly to MACE. 
10.3.7 Analysis of other variables 
A full description of all other analyses will be provided in the SAP. 
10.4 Interim analyses 
No interim analysis is planned for this study. 
10.5 Sample size 
The sample size is driven by the power for the key secondary endpoint. The within-group 
standard deviation for the change from Week 36 to Week 40 in mean trough SiSBP as 
measured by AOBPM is expected to be around 15 mmHg (based on study AC-080A201). 
A difference vs placebo (‘delta’) of at least 5 mmHg is considered clinically relevant.  
With a type I error of 0.05 (two-sided; if both H10 and H20 have been rejected), the size of 
the mFAS needed for 90% power to detect a difference of 5 mmHg between aprocitentan 
25 mg and placebo would be 380 subjects (190 in each of the two groups in the DB-WD 
part). The sample size is based on the t-test but provides similar power for the mixed model. 
The anticipated drop-out rate is 37% in the 9 months between Randomization and start of 
the DB-WD part (based on the AC-080A201 study). In order to have 380 subjects in the 


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DB-WD part a total of 600 subjects need to be randomized (200 in each of the three groups 
in the DB part of the study).  
For the change from baseline to Week 4 in mean trough SiSBP as measured by AOBPM 
(primary endpoint) the clinically relevant difference vs placebo is around 6 mmHg. With 
200 subjects per group in the DB part, the power to detect this difference is well over 90%. 
Table 5 
Power to detect a treatment difference for the primary endpoint 
Delta (mmHg) 
5.5 
6.0 
6.5 
Power (alpha=0.025 two-sided) 
92% 
96% 
98% 
In case only one of the two doses in the DB part is statistically significantly better than 
placebo on the primary endpoint, the secondary endpoint must be tested at alpha=0.025 
(two-sided). In that case the power for the DB-WD part is 84%. However, testing at 
alpha=0.025 is less likely than testing at alpha=0.05 (under the assumptions made in the 
sample size calculations the probabilities are approximately 80% and 20%, respectively). 
On average, the power for the DB-WD part is approximately 88%. 
If the drop-out rate is greater than anticipated the sample size may be increased in order to 
ensure sufficient power for the DB-WD part. The sample size will not be decreased 
below 600. 
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timelines of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of the data. Data reported in the eCRF derived 
from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture. The investigator and site personnel 
will be trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to US 
21 CFR Part 11). 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study.  


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11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
the sponsor and any vendors or CROs, subjects must be identified only by number and 
never by their name or initials, date of birth, hospital numbers, or any other personal 
identifier. The investigator/delegate must keep a subject identification code list at the site, 
showing the screening/randomization number, the subject’s name, date of birth, and 
address or any other locally accepted identifiers. Documents identifying the subjects (e.g., 
signed ICFs) must not be sent to the sponsor, any vendor or CROs, and must be kept in 
strict confidence by the investigator/delegate.  
11.3 Database management 
eCRFs will be used for all subjects. The investigators will have write access to the site 
eCRF data until the database is locked. Thereafter, they will have read-only access, until 
they receive an electronic copy of the site eCRFs. The eCRF must be kept current to reflect 
subject status at any time point during the course of the study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by the sponsor 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. If discrepant data are detected, a query specifying the issue and requesting 
clarification will be issued and visible to the investigator/delegate via the eCRF. All 
electronic queries visible in the system either require a data correction (when applicable) 
and a response from the investigator/delegate to clarify the queried data directly in the 
eCRF, or simply a data correction in the eCRF. The investigator/delegate must, on request, 
supply the sponsor with any required background data from the study documentation or 
clinical records. This is particularly important when errors in data transcription are 
suspected. In the case of health authority queries, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
This process will continue until database lock. 
Laboratory samples, ECGs, AOBPM and ABPM will be processed through a central 
laboratory or vendor and the results of the randomized subjects will be electronically sent 
to the sponsor. 
AEs and medical history are coded according to the latest MedDRA version used by the 
sponsor. Medications are coded according to the latest WHO Drug Dictionary version used 
by the sponsor. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made as described in the 


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appropriate sponsor QS docs. After database lock, the investigator will receive the CRFs 
of the subjects of his/her site (including the audit trail) as a portable document format file. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
The sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki”, and 
with the laws and regulations of the country in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board (IEC/IRB) 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed, and the date of 
approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  
If a member of the site study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
12.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH-GCP and Declaration of Helsinki guidelines and local regulations from each 
individual subject participating in this study and/or his/her legally designated 
representative. The investigator/delegate must explain to subjects that they are completely 
free to refuse to enter the study, or to voluntarily withdraw from the study at any time for 
any reason without having to provide any justification. Special attention shall be paid to 
the information needs of specific subject populations and of individual subjects, as well as 
to the methods used to give the information. Adequate time shall be given for the subject 
to consider his or her decision to participate in the study and it shall be verified that the 
subject has understood the information (e.g., by asking the subject to explain what is going 
to happen).  
The ICF will be provided in the country local language(s). 


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Site personnel authorized (according to local regulation) to participate in the consent 
process and/or to obtain consent from the subject will be listed on the Delegation of 
Authority form. 
The subject and authorized site personnel listed on the Delegation of Authority form must 
sign, personally date, and time (if the first study-mandated procedure is to be performed on 
the same day informed consent is obtained) the ICF before any study-related procedures 
(i.e., any procedures required by the protocol) begin.  
The informed consent process must be fully documented in the subject’s medical records. 
This must include at a minimum the study reference, the subject number, the date and, if 
applicable, time when the subject was first introduced to the study, the date and, if 
applicable, time of consent, who participated in the consent discussion, who consented the 
subject, and any additional person present during the consent process (e.g., subject’s family 
member[s]), and the information that a copy of the signed ICF was given to the subject. 
12.4 Compensation to subjects and investigators 
The sponsor provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims that 
arise from malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB and/or the 
regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform the sponsor or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to the 
sponsor or (overruling) local requirements. 
All protocol deviations will be reported in the CSR. IECs/IRBs will be provided with 
listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according 
to their requirements. 


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12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. Several attributes are considered of universal importance to 
source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
the sponsor’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the site for any or all of the documents, 
special arrangements, respecting the data confidentiality, must be made between the 
investigator and the sponsor to store these documents outside the site, so that they can be 
retrieved in the event of a regulatory inspection. No study document should be destroyed 
without prior written approval from the sponsor. Should the investigator wish to assign the 
study records to another party, or move them to another location, the sponsor must be 
notified in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the CRA has been provided 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 CRA could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the CRA. The print-outs must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per the sponsor instructions. If it were not possible for the 


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


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12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is filed. 
This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. 
The ISF must be kept by the site for as long as is necessary to comply with the sponsor’s 
requirements (i.e., as specified in the clinical study agreement), ICH-GCP and national 
and/or international regulations, whichever would be the longest period. If the site needs 
to transfer the ISF to another location and/or if site facility can no longer store the ISF, the 
PI must immediately inform the sponsor. 
If the PI changes or if the site relocates the CRA must be notified as soon as possible. 
12.10 Audit 
The sponsor representatives may audit the investigator site (during the study or after its 
completion). The purpose of this visit will be to determine the investigator’s adherence to 
ICH-GCP, the protocol, and applicable regulations; adherence to the sponsor requirements 
(e.g., standard operating procedures) will also be verified. Prior to initiating this audit, the 
investigator will be contacted by the sponsor to arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during the 
study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform the sponsor (usually via the CRA) that such a request has been 
made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 


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12.12 Reporting of study results and publication 
The sponsor will post the key elements of this protocol and the summary of results within 
the required timelines on publicly accessible databases (e.g., clinicaltrials.gov, EU 
database), as required by law and regulation. 
Study results will be documented in a CSR that will be signed by the sponsor’s 
representatives and the Coordinating Investigator. 
In accordance with the Good Publication Practices and ethical practice as outlined in 
internationally recognized guidance documents (e.g., European Medical Writers 
Association, American Medical Writers Association, International Society for Medical 
Publication Professionals), the results of the study will be submitted for publication in a 
peer-reviewed journal. Study results can be submitted for presentation at a congress before 
submission to a peer-reviewed journal. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 

substantial contributions to the conception or design of the study, or the acquisition,
analysis, or interpretation of data; and

drafting of the publication or critical review for important intellectual content; and

providing final approval of the version to be published; and

agreement to be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appropriately
investigated and resolved.
The list of authors of any publication of study results may include representatives of the 
sponsor and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
the sponsor for review at least 30 days prior to submission for publication or presentation 
at a congress. Upon review, the sponsor may provide comments, and may also request 
alterations and/or deletions for the sole purpose of protecting its confidential information 
and/or patent rights. Neither the institution nor the investigator should permit publication 
during such a review period. 


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(ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 
2011;57(6):1069–75.  
[Weber 2009] Weber MA, Black H, Bakris G, Krum H, Linas S, Weiss R, et al. A selective 
endothelin-receptor antagonist to reduce blood pressure in patients with 
treatment-resistant hypertension: a randomized, double-blind, placebo-controlled 
trial. Lancet. 2009;347:1423–31. 
[Weber 2014] Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, 
et al. Clinical Practice Guidelines for the Management of Hypertension in the 
Community. J Clin Hypertens. 2014;16(1):14–26. 


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[Whelton 2017] Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison 
Himmelfarb 
C. 
2017 
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ 
ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and 
Management of High Blood Pressure in Adults: A Report of the American College 
of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. Hypertension. 2017 Nov 13 PMID: 29133356. ePub ahead of print. 
[White 2014] White WB, Turner JR, Sica DA, Bisognano JD, Calhoun DA, Townsend RR, 
et al. Detection, evaluation, and treatment of severe and resistant hypertension: 
Proceedings from an American Society of Hypertension Interactive Forum held in 
Bethesda, MD, USA, October 10th 2013. J Am Soc Hypertension. 
2014;8(10);743-57. 
[Williams 2012] in BMJ 2012;345:e7473 doi: 10.1136/bmj.e7473 (Published 20 
November 2012). 
[Williams 2015] Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, 
et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the 
optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, 
double-blind, crossover trial. Lancet. 2015;386(10008):2059–68. 
[Williams 2018] Williams B, Mancia G, Spiering W, Agabiti Rosei E, Aziz M, Burnier M, 
et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur 
Heart J 2018;39(33):3021–3104. 
[Wright 2015] Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, 
Rocco MV, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure 
Control. N Engl J Med. 2015;373(22):2103–16. 


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14 APPENDICES 
Appendix 1 
Forbidden drugs 
A) Medication which may affect BP:

Inhibitors of vascular endothelial growth factor such as bevacizumab, or tyrosine
kinase inhibitors such as sunitinib and sorafenib,

Immunosuppressive agents: cyclosporine and tacrolimus (topical applications of
tacrolimus are permitted),

Sympathomimetics (any formulation),
o
Intermittent (not daily) use of topical (nasal/inhalers/drops) decongestants
is permitted, except within 3 days prior to a study visit.

Diet pills: phenylpropanolamine and sibutramine,

Stimulants: amphetamines and cocaine (topical applications for local anesthesia are
permitted),

Herbal supplements: ephedra, ma huang, Yohimbine,

Systemic corticosteroids (topical nasal/inhalers/drops/local injection applications
are permitted),

CYP17A1 inhibitors such as abiraterone,

Phosphodiesterase type 5 inhibitors: except intermittent (not daily) use of sildenafil,
vardenafil or tadalafil (e.g., 
®, 
®, 
®) within 5 days prior to a
study visit,

Licorice.
For details information, please refer to Kassel et al [Kassel 2015]. 
B) Antihypertensive therapies except standardized background antihypertensive therapy,
rescue medication including diuretics, and diuretics for treatment of clinically relevant
fluid retention [see Section 5.2.2, 5.2.3.1, and 5.2.3.2], such as:

Drugs that target the renin-angiotensin system;
o
ACEIs (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril,
moexipril, perindropril, quinapril, ramipril, trandolapril).
o
ARBs (e.g., azilsartan, candesartan, eprosartan, ibresartan, losartan,
olmesartan, telmisartan).


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o Direct renin inhibitor (e.g., aliskiren).  
 Diuretics;  
o Thiazide 
and 
thiazide 
like 
diuretics 
(e.g., 
bendrofluazide, 
bendroflumethiazide, chlorthalidone, hydroflumethiazide, indapamide, 
methylclothiazide, metolazone, polythiazide),  
o Loop diuretics (e.g., bumetanide, furosemide, piretanide, torsemide),  
o Potassium-sparing diuretics (e.g., amiloride, eplerenone, spironolactone, 
triamterene).  
 CCBs; 
o Dihydropyridines (e.g., felodipine, isradipine, nicardipine, nifedipine, 
nitrendipine, nisoldipine). 
o Non dihydropyridines (e.g., diltiazem, verapamil). 
 
 Alpha-adrenergic receptors blockers (e.g., doxazosin, phenoxybenzamine, 
phentholamine, prazosin, terazosin), with the exception of alfuzosin and tamsulosin 
for prostatic symptoms [see Section 5.2.3], 
 Vasodilators (e.g., hydralazine, minoxidil), 
 Central alpha-agonists (e.g., clonidine, clonidine patch, guanfacine, methyldopa, 
rilmenidine), 
 Adrenergic depleters (e.g., reserpine).  
 
C) ERAs (e.g., bosentan, macitentan, ambrisentan). 
For detailed information, please refer to American Society of Hypertension guidelines 
[Weber 2014].