Multi-center, Blinded, Randomized, Parallel-group, Phase 3 Study With Aprocitentan in Subjects With Resistant Hypertension (RHT)
Phase: PHASE3
Conditions: Resistant Hypertension
Sponsor: Idorsia Pharmaceuticals Ltd.

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.