A Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase 3 Study to Assess the Efficacy and Safety of Clazosentan in Preventing Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI), in Adult Subjects With Aneurysmal Subarachnoid Hemorrhage (aSAH)
Phase: PHASE3
Conditions: Aneurysmal Subarachnoid Hemorrhage
Sponsor: Idorsia Pharmaceuticals Ltd.

Cover page 
ID-054-304 
 
Addendum to protocol: Exceptional measures to ensure subject safety and 
counteract potential trial conduct disruption due to the COVID-19 pandemic 
 
 
Official Title: 
A Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-
group, Phase 3 Study to Assess the Efficacy and Safety of Clazosentan in Preventing 
Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI), in Adult Subjects With 
Aneurysmal Subarachnoid Hemorrhage (aSAH) 
 
ClinicalTrials.gov Identifier: 
NCT03585270 
 
Date of document: 
12 May 2020 

 
 
 
 
 
 
 
 
 
 
 
ADDENDUM TO PROTOCOL 
ID-054-304 
 
 
Exceptional measures to ensure subject safety and counteract 
potential trial conduct disruption due to the  
COVID-19 pandemic 
 
 
 
 
Document Number: D-20.085 
 
 
12 May 2020 
 
 
 
 
 
 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 
 
 

Clazosentan / ACT-108475 
ID-054-304, REACT  
12 May 2020, page 2/7 
Confidential 
Addendum to protocol:  
COVID-19 pandemic 
Doc No D-20.085 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ........................................................... 3 
1 
INTRODUCTION ........................................................................................................ 4 
2 
RECOMMENDATIONS AND INSTRUCTIONS ...................................................... 5 
2.1 
MoCA testing and outcome assessments at the Week 12 visit ...................... 5 
2.2 
Safety follow-up at Week 12 and Week 24 ................................................... 5 
2.3 
Provisions for subjects infected with SARS-CoV-2 during recruitment 
hold ................................................................................................................ 6 
2.4 
Reporting of protocol deviations related to the COVID-19 pandemic .......... 6 
2.5 
Monitoring ..................................................................................................... 6 
 
 
 
 
 

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Addendum to protocol:  
COVID-19 pandemic 
Doc No D-20.085 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE Adverse event 
COVID-19 Coronavirus disease 2019 
CRA Clinical research associate 
eCRF Electronic case report form 
EOS End-of-Study 
GCP Good Clinical Practice 
GOSE/mRS Glasgow Outcome Scale / Modified Rankin Scale 
ICH International Council for Harmonisation 
ICU Intensive care unit 
IEC Independent Ethics Committee 
IRB Institutional Review Board 
MoCA Montreal Cognitive Assessment 
PD Protocol deviation 
QoLs Quality of life assessments 
SAE Serious adverse events 
SDV Source data verification 
WHO World Health Organization 
 
 

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Addendum to protocol:  
COVID-19 pandemic 
Doc No D-20.085 
 
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), on 19 March 2020 Idorsia put the recruitment for the ID-054-304 
(REACT) study on hold temporarily. Health authorities and IECs/IRBs have been 
informed, as required. This decision was a precautionary measure taken to spare intensive 
care resources at the participating sites. As a result, subject safety, trial integrity and 
interpretability can also be preserved. 
A recruitment hold communication letter was sent to the study investigators on 20 March 
2020.  
Sites were informed that patients who had already signed an informed consent form and 
were therefore in screening could still be randomized. Investigators were instructed that 
any randomized subjects, including the ones in the treatment period, should continue their 
study participation. This was recommended as for the few subjects with treatment ongoing 
the monitoring of safety during ICU/hospital stay was ensured, and the risk of any of these 
subjects getting infected with COVID-19 during the maximum 14 days of treatment 
administration plus 24-hour follow-up period was considered minimal. Therefore, the 
overall benefit/risk of continuing study drug was considered favorable. At the time of 
issuing this protocol addendum, all subjects have completed their study treatment and no 
COVID-19 related complications were reported by the sites. 
Data collection for subjects enrolled was asked to be completed to the extent possible in 
accordance with the study protocol. Instructions were issued to record PDs due to the 
COVID-19 situation and continuing to report them as per clinical trial requirements to 
Idorsia, IEC/IRB, regulatory authority, and/or any other applicable parties.  
Sites were reminded that the Week 12 and Week 24 visits can be done remotely as per 
protocol. 
Instructions regarding the Week 12 MoCA testing, and instances when the entire Week 12 
visit and the safety follow-up at either at Week 12 or Week 24 post-aSAH become 
compromised due to COVID-19 restrictions are provided in Section 2.  
Additionally, provisions are given for subjects infected with SARS-CoV-2 after 
recruitment has resumed by emphasizing applicable sections already present in the 
protocol.  
All PDs related to the COVID-19 crisis will be identified and tracked by Idorsia. 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 PDs continue to be collected as per 
original protocol definition, and will be identified as due to COVID-19 pandemic even 
after the implementation of this addendum. 

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Addendum to protocol:  
COVID-19 pandemic 
Doc No D-20.085 
 
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. 
2 
RECOMMENDATIONS AND INSTRUCTIONS 
2.1 MoCA testing and outcome assessments at the Week 12 visit 
The preferred option is to maintain the Week 12 visit as a face-to-face on-site visit, 
provided that the subject is allowed as per COVID-19 restrictions and can travel to the site. 
To ensure safety of the subject on his/her way to the site, the site staff will remind the 
subject to adhere to local laws and recommendations (e.g., not using public transportation). 
Alternatively, subjects can use taxis or private cars, the cost of which will be reimbursed 
by Idorsia. 
If the subject cannot return to the site due to COVID-19 pandemic-related reasons, the visit 
should be conducted remotely within the protocol-defined time window. However, as per 
protocol the MoCA can only be performed face-to-face. Remote administration will not be 
allowed during the COVID-19 pandemic. Instead, if MoCA face-to-face testing could not 
be done at the time of the Week 12 visit, the testing should be performed at the earliest 
face-to-face opportunity, even if it is outside of the protocol-defined time window, as soon 
as possible, and at the latest at the time of the EOS visit at 24 weeks post-aSAH. If at the 
due time of the visit the MoCA assessment could not be performed because the condition 
of the subject does not allow for testing (e.g., Glasgow Coma Scale estimated as ≤ 13), the 
assessment should be considered as not done and the corresponding reason(s) must be 
entered into the applicable eCRF form(s). 
Should the self-completion of the QoLs (Stroke Specific Quality of Life, Oxford 
Participation and Activities Questionnaire, EQ-5D) be compromised given the 
circumstances (e.g., questionnaires cannot be delivered by post), any of the assessments 
can be performed out-of-window, as soon as possible before the EOS visit at 24 weeks 
post-aSAH, either remotely or face-to-face.  
Postponing the Week 12 assessments is only allowed because of logistical restrictions 
due to the COVID-19 pandemic.  
2.2 Safety follow-up at Week 12 and Week 24  
If an ongoing AE requires follow-up as per protocol sections 9.2.1 and 9.2.2 at either the 
Week 12 or Week 24 visit, including follow-up of laboratory abnormalities, the subject 
should be asked to return to the hospital following evaluation of the risk with regards to 
safety of the travel. If the subject cannot or is not willing to return because of the 
COVID-19 pandemic, the option of referring the patient for follow-up to an alternative 
hospital or local laboratory should be evaluated.  

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Addendum to protocol:  
COVID-19 pandemic 
Doc No D-20.085 
 
If the urine pregnancy test for women of childbearing potential due at the Week 12 visit 
cannot be delivered to the subject’s home, the use of a self-purchased pregnancy test is 
allowed, for which the subject will be reimbursed.  
2.3 Provisions for subjects infected with SARS-CoV-2 during recruitment 
hold 
Testing for SARS-CoV-2 should follow local guidance. Mandatory testing is not required 
for this study. No specific provisions are foreseen if a subject is found positive for 
SARS-CoV-2, during hospitalization or the period between discharge from the hospital 
and EOS. 
Idorsia has evaluated the potential drug-drug interactions with the current available most 
frequently used medications for COVID-19 (e.g., remdesivir, lopinavir/ritonavir, IFN 
beta1b, 
corticosteroids, 
hydroxychloroquine). 
Clazosentan 
is 
a 
substrate 
of 
OATP1B1/1B3, therefore inhibitors/inducers, i.e.: lopinavir/ritonavir is contraindicated. 
As already defined in the protocol, subjects for whom the use of OATP inhibitors is 
foreseen are excluded from the study [protocol section 4.4]. Additionally, OATP inhibitor 
administration is forbidden until Day 14 post-study drug initiation [protocol section 5.2.4]. 
If their use is inevitable, study drug must be permanently discontinued [protocol 
section 5.1.3.4.1].  
Based on our current knowledge, the rest of the assessed anti-COVID-19 drugs are not 
expected to mutually affect their PKproperties based on an effect on metabolizing enzymes 
or transporters. Clazosentan has no perpetrator potential on enzymes or transporters. 
Information about COVID-19, whether confirmed with a positive SARS-CoV-2 test result 
or not, and its corresponding diagnosis (symptoms) as well as administered medications 
will be collected on the AE and Concomitant Medication pages of the eCRF [see protocol 
sections 9 and 5.2.5 for reporting procedures].  
2.4 Reporting of protocol deviations related to the COVID-19 pandemic 
PDs due to the COVID-19 pandemic 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 the COVID-19 pandemic must be documented according to ICH GCP 
section 4.5.3 and clearly recorded as related to the COVID-19 pandemic. All PDs will be 
reported to the sponsor, IEC/IRB, regulatory authorities and/or any other applicable parties, 
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 and with the IEC/IRB, the CRA will conduct 
remote monitoring and remote SDV, provided that subject confidentiality is maintained 

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Addendum to protocol:  
COVID-19 pandemic 
Doc No D-20.085 
 
throughout the process [as per protocol Section 11.2] and all local approvals to do so are 
in place, as applicable. If remote monitoring or remote SDV are not allowed, alternatives 
as applicable according to local regulations may be agreed with the principal investigator 
to ensure data integrity.