Conditions: Aneurysmal Subarachnoid Hemorrhage
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 409
Healthy volunteers: no

Brief summary:
This study will evaluate if clazosentan (on top of normal routine medical care) can reduce the risk of developing complications related to cerebral vasospasm and permanent brain damage as compared to normal routine medical care alone.

Detailed description:
When a blood vessel just outside the brain bursts and causes bleeding onto its surface, the space surrounding the brain (the subarachnoid space) fills with blood. This condition is called subarachnoid hemorrhage. The bleeding due to the rupture of a pouch-like structure or a bulge (called an aneurysm) that formed on one of the blood vessels is condition called aneurysmal subarachnoid hemorrhage (aSAH).

In this study, clazosentan is being tested against normal routine medical care to determine if clazosentan can reduce the risk of developing complications related to vasospasm and permanent brain damage.

Participation will last for approximately 6 months from the episode of bleeding. For subjects randomized in the high-risk prevention group, treatment will start within 96 hours following the time of the aneurysm rupture, and be administered where possible, for 14 days. For subjects randomized in the early treatment group, treatment must begin within 24 hours of the time of the angiogram documenting the cerebral vasospasm necessary for entry into the study. Treatment will be administered for a minimum of 6 days and a maximum of 14 days. Recruitment in the early treatment group has been discontinued.

The end-of-study will be conducted as a telephone interview 6 months after the episode of bleeding.

Arms:
arm 1: Participants will receive clazosentan for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH). arm 2: Participants will receive clazosentan matching-placebo for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH).

Interventions: intervention 1: Clazosentan intervention 2: Placebo
Intervention descriptions: intervention 1: Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days. intervention 2: Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.

Protocol document:
Prot_003.pdf: 
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 
 
 


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Addendum to protocol:  
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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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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:  
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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:  
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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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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. 

Prot_000.pdf: 
Cover page 
ID-054-304 
 
Protocol 
 
 
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: 
18 Feb 2022 


 
 
TPL-100601_v03 
Clazosentan / ACT-108475 
 
Aneurysmal Subarachnoid Hemorrhage 
Protocol ID-054-304 
 
REACT: pRevention and trEatment of vAsospasm with ClazosenTan 
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)  
 
Study Phase: 
3 
EudraCT Number: 
2018-000241-39 
Status and version: 
Final Version 7  
Date: 
18 February 2022 
Document type: 
Global protocol 
Idorsia document number  
(Doc No.): 
D-22.069 
 
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. 
 
 


Clazosentan / ACT-108475 
Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
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Doc No D-22.069 
 
 
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 
telephone number:  
The telephone number 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. 
 
 




Clazosentan / ACT-108475 
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Protocol ID-054-304, REACT 
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Doc No D-22.069 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
Treatment name / number 
Clazosentan / ACT-108475 
Indication 
Aneurysmal subarachnoid hemorrhage 
Protocol number, study acronym, study title 
ID-054-304, REACT (pRevention and trEatment of vAsospasm with ClazosenTan) 
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). 
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 well-being of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. 
 
Principal 
Investigator 
Country 
Site 
number 
Town 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 


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Doc No D-22.069 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ......................................................... 12 
SUBSTANTIAL GLOBAL AMENDMENT 6 ................................................................ 16 
PROTOCOL SYNOPSIS ID-054-304 .............................................................................. 21 
PROTOCOL ..................................................................................................................... 39 
1 
BACKGROUND ........................................................................................................ 39 
1.1 
Subarachnoid hemorrhage ........................................................................... 39 
1.2 
Medical management of aSAH and its vasospastic complications ............. 39 
1.3 
Unmet medical need in aSAH ..................................................................... 40 
1.4 
Clazosentan .................................................................................................. 40 
1.4.1 
Mechanism of action ........................................................................ 40 
1.4.2 
Nonclinical summary ....................................................................... 41 
1.4.3 
Clinical summary ............................................................................. 41 
1.4.4 
Clazosentan dose rationale ............................................................... 43 
1.5 
Rationale of the study .................................................................................. 44 
1.6 
Summary of known and potential risks and benefits ................................... 44 
2 
STUDY OBJECTIVES .............................................................................................. 46 
2.1 
Primary objective ......................................................................................... 47 
2.2 
Secondary objectives ................................................................................... 47 
2.3 
Other objectives ........................................................................................... 47 
3 
OVERALL STUDY DESIGN AND PLAN .............................................................. 47 
3.1 
Study design ................................................................................................ 47 
3.1.1 
Study periods ................................................................................... 48 
3.1.2 
Study duration .................................................................................. 52 
3.2 
Overall study design rationale ..................................................................... 52 
3.3 
Study committees ........................................................................................ 53 
3.3.1 
Independent Data Monitoring Committee ....................................... 53 
3.3.2 
Independent Radiology Committee ................................................. 53 
3.3.3 
Clinical Event Committee ................................................................ 53 
4 
STUDY POPULATION ............................................................................................ 54 
4.1 
Selection of study population ...................................................................... 54 


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4.2 
Rationale for the selection of the study population ..................................... 54 
4.3 
Inclusion criteria .......................................................................................... 56 
4.4 
Exclusion criteria ......................................................................................... 57 
4.5 
Definition of childbearing potential ............................................................ 60 
4.6 
Breastfeeding women .................................................................................. 60 
4.7 
Contraceptive requirements for women of childbearing potential .............. 60 
4.8 
Contraceptive requirements for men ........................................................... 61 
5 
TREATMENTS ......................................................................................................... 62 
5.1 
Study treatment ............................................................................................ 62 
5.1.1 
Investigational treatment and matching placebo ............................. 62 
5.1.2 
Treatment assignment ...................................................................... 62 
5.1.3 
Study treatment dosing, preparation and administration ................. 62 
5.1.3.1 
Study drug dose ...................................................................... 62 
5.1.3.2 
Study drug preparation ........................................................... 63 
5.1.3.3 
Study drug administration ...................................................... 63 
5.1.3.4 
Premature discontinuation of study treatment ........................ 66 
5.1.4 
Blinding ........................................................................................... 67 
5.1.5 
Unblinding ....................................................................................... 68 
5.1.5.1 
Unblinding for final analyses ................................................. 68 
5.1.5.2 
Unblinding for suspected unexpected serious adverse 
reactions .................................................................................. 68 
5.1.5.3 
Emergency procedure for unblinding ..................................... 68 
5.1.6 
Study treatment supply .................................................................... 69 
5.1.6.1 
Study treatment packaging and labeling ................................ 69 
5.1.6.2 
Study treatment distribution and storage ................................ 69 
5.1.6.3 
Study treatment dispensing .................................................... 70 
5.1.6.4 
Study treatment return and destruction .................................. 70 
5.1.7 
Study treatment accountability and compliance with study 
treatment .......................................................................................... 70 
5.1.7.1 
Study treatment accountability ............................................... 70 
5.1.7.2 
Study treatment compliance ................................................... 70 
5.2 
Previous and concomitant therapy ............................................................... 71 
5.2.1 
Definitions ....................................................................................... 71 
5.2.2 
Concomitant therapy required to control blood pressure and 
fluid status (mandatory compliance with the Patient 
Management Guidelines) ................................................................. 71 
5.2.3 
Allowed concomitant therapy .......................................................... 71 
5.2.3.1 
Local standard of care ............................................................ 71 
5.2.3.2 
Rescue therapy ....................................................................... 72 


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5.2.4 
Forbidden concomitant therapy ....................................................... 72 
5.2.5 
Reporting of previous/concomitant therapy in the eCRF ................ 73 
6 
STUDY ENDPOINTS ............................................................................................... 74 
6.1 
Efficacy endpoints ....................................................................................... 74 
6.1.1 
Primary efficacy endpoint ................................................................ 74 
6.1.2 
Secondary efficacy endpoints .......................................................... 75 
6.1.2.1 
Main secondary endpoint ....................................................... 75 
6.1.2.2 
Other secondary endpoints ..................................................... 76 
6.1.3 
Exploratory efficacy endpoints ........................................................ 76 
6.1.3.1 
Cognition endpoints ............................................................... 76 
6.1.3.2 
Other efficacy endpoints ........................................................ 76 
6.2 
Safety endpoints .......................................................................................... 76 
6.3 
Quality of Life endpoints ............................................................................. 77 
6.4 
Pharmaco-economic endpoints .................................................................... 77 
6.5 
Biomarker endpoints .................................................................................... 77 
6.6 
Rationale for primary and secondary efficacy endpoints ............................ 77 
6.6.1 
Rationale for the choice of the primary efficacy endpoint .............. 77 
6.6.2 
Rationale for the choice of secondary efficacy endpoints ............... 78 
6.6.2.1 
Occurrence of clinically relevant cerebral infarction at 
Day 16 post-study drug initiation defined as: all-cause 
cerebral infarction ≥ 5 cm3 or cerebral infarction < 5 cm3 
in subjects with clinical deterioration due to DCI .................. 78 
6.6.2.2 
Modified Rankin Scale and Glasgow Outcome Scale 
Extended ................................................................................. 79 
7 
STUDY PERIODS, VISITS AND ASSESSMENTS ................................................ 80 
7.1 
Study periods and “visits” ........................................................................... 80 
7.1.1 
Screening/re-screening ..................................................................... 87 
7.1.1.1 
Screening period ..................................................................... 87 
7.1.1.2 
Re-screening ........................................................................... 87 
7.1.1.3 
Randomization without subsequent start of study drug ......... 87 
7.1.2 
Treatment period .............................................................................. 88 
7.1.3 
24-hour safety follow-up period ...................................................... 88 
7.1.4 
Observation period for primary endpoint ........................................ 89 
7.1.5 
Extended follow-up period .............................................................. 89 
7.1.6 
Unscheduled visits ........................................................................... 89 
7.1.7 
Week 12 visit ................................................................................... 89 
7.1.8 
EOS visit (individual subject) .......................................................... 90 
7.1.9 
EOS (study level) ............................................................................. 90 


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7.2 
Study assessments ........................................................................................ 90 
7.2.1 
Demographics / baseline disease characteristics ............................. 91 
7.2.1.1 
aSAH history .......................................................................... 92 
7.2.1.2 
Data to be collected for screening failure subjects ................. 92 
7.2.2 
Efficacy assessments ........................................................................ 93 
7.2.2.1 
Neurological assessment scales .............................................. 93 
7.2.2.2 
Primary endpoint assessments ................................................ 99 
7.2.2.3 
Cerebral angiograms ............................................................. 103 
7.2.2.4 
Cerebral CT scans ................................................................ 105 
7.2.2.5 
Combined Glasgow Outcome Scale Extended / modified 
Rankin Scale interview ......................................................... 107 
7.2.2.6 
Montreal Cognitive Assessment ........................................... 107 
7.2.3 
Safety assessments ......................................................................... 108 
7.2.3.1 
Weight and height ................................................................ 108 
7.2.3.2 
Vital signs ............................................................................. 108 
7.2.3.3 
Intracranial pressure ............................................................. 109 
7.2.3.4 
Central venous pressure ........................................................ 109 
7.2.3.5 
Body temperature ................................................................. 109 
7.2.3.6 
24-hour fluid intake and balance .......................................... 109 
7.2.3.7 
Electrocardiogram parameters .............................................. 110 
7.2.4 
Laboratory assessments ................................................................. 110 
7.2.4.1 
Types of laboratory .............................................................. 110 
7.2.4.2 
Laboratory tests .................................................................... 111 
7.2.5 
Quality of Life assessments ........................................................... 113 
7.2.5.1 
Stroke Specific Quality of Life ............................................ 113 
7.2.5.2 
Oxford Participation and Activities Questionnaire .............. 114 
7.2.5.3 
EQ-5D .................................................................................. 115 
7.2.6 
Pharmaco-economic assessments .................................................. 116 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ....................................................................................................................... 116 
8.1 
Study completion as per protocol .............................................................. 116 
8.2 
Premature withdrawal from study ............................................................. 116 
8.3 
Premature termination or suspension of the study ..................................... 117 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ........................................................................................................... 118 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ........................ 118 
9.1 
Safety definitions ....................................................................................... 118 
9.1.1 
Definition of adverse events .......................................................... 118 


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9.1.2 
Definition of serious adverse events .............................................. 119 
9.1.3 
Definition of waived serious adverse events ................................. 120 
9.1.4 
Definition of suspected unexpected serious adverse reactions ...... 120 
9.1.5 
Intensity of adverse events ............................................................. 121 
9.1.6 
Relationship to study treatment ..................................................... 121 
9.1.7 
Relationship to protocol-mandated procedure ............................... 121 
9.2 
Time period and frequency for adverse event / serious adverse event 
assessment and follow-up .......................................................................... 121 
9.2.1 
Follow-up of adverse events .......................................................... 122 
9.2.2 
Follow-up of serious adverse events .............................................. 122 
9.3 
Reporting procedures ................................................................................. 122 
9.3.1 
Reporting of adverse events ........................................................... 122 
9.3.1.1 
Reporting of acute respiratory distress syndrome ................ 122 
9.3.2 
Additional reporting procedure for serious adverse events ........... 123 
9.4 
Pregnancy .................................................................................................. 124 
9.4.1 
Reporting of pregnancy ................................................................. 124 
9.4.2 
Follow-up of pregnancy ................................................................. 124 
9.5 
Breastfeeding women ................................................................................ 124 
9.6 
Reporting of study treatment overdose, misuse, abuse and medication 
errors .......................................................................................................... 124 
9.7 
Study safety monitoring ............................................................................. 125 
10 STATISTICAL METHODS .................................................................................... 125 
10.1 
Analysis sets .............................................................................................. 125 
10.1.1 
Screened analysis set ..................................................................... 125 
10.1.2 
Randomized analysis set ................................................................ 125 
10.1.3 
Full analysis set .............................................................................. 125 
10.1.4 
Per-protocol analysis set ................................................................ 126 
10.1.5 
Safety analysis set .......................................................................... 126 
10.1.6 
Other analysis sets ......................................................................... 126 
10.1.7 
Usage of the analysis sets .............................................................. 126 
10.2 
Variables .................................................................................................... 127 
10.2.1 
Primary efficacy variable ............................................................... 127 
10.2.2 
Secondary efficacy variables ......................................................... 127 
10.2.2.1 
Main secondary variable ...................................................... 127 
10.2.2.2 
Other secondary efficacy variable ........................................ 128 
10.2.3 
Safety variables .............................................................................. 128 
10.2.3.1 
Adverse events ..................................................................... 128 
10.2.3.2 
Laboratory data ..................................................................... 128 
10.3 
Description of statistical analyses .............................................................. 129 


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10.3.1 
Overall testing strategy .................................................................. 130 
10.3.2 
Analysis of the primary efficacy variable ...................................... 131 
10.3.2.1 
Hypotheses ........................................................................... 131 
10.3.2.2 
Primary statistical analysis ................................................... 131 
10.3.2.3 
Handling of missing data ...................................................... 132 
10.3.2.4 
Supportive analyses .............................................................. 132 
10.3.2.5 
Sensitivity analysis ............................................................... 133 
10.3.2.6 
Subgroup analyses ................................................................ 133 
10.3.3 
Analysis of the secondary efficacy variables ................................. 135 
10.3.3.1 
Occurrence of clinically relevant cerebral infarction at 
Day 16 post-study drug initiation defined as: all-cause 
cerebral infarction ≥ 5 cm3 or cerebral infarction < 5 cm3 
in subjects with clinical deterioration due to DCI ................ 135 
10.3.3.2 
Clinical outcome as assessed by the mRS at Week 12 
post-aSAH ............................................................................ 136 
10.3.3.3 
Clinical outcome as assessed by the GOSE at Week 12 
post-aSAH ............................................................................ 137 
10.3.4 
Analysis of other efficacy variables ............................................... 138 
10.3.5 
Analysis of the safety variables ..................................................... 138 
10.3.5.1 
Adverse events ..................................................................... 138 
10.3.5.2 
Laboratory data ..................................................................... 139 
10.3.6 
Analysis of other variables ............................................................ 139 
10.4 
Interim analyses ......................................................................................... 139 
10.5 
Sample size ................................................................................................ 139 
10.5.1 
Primary efficacy objective ............................................................. 140 
10.5.2 
Secondary efficacy objective (main) ............................................. 140 
11 DATA HANDLING ................................................................................................. 140 
11.1 
Data collection ........................................................................................... 140 
11.2 
Maintenance of data confidentiality .......................................................... 141 
11.3 
Database management ............................................................................... 141 
12 PROCEDURES AND GOOD CLINICAL PRACTICE .......................................... 142 
12.1 
Ethics and Good Clinical Practice ............................................................. 142 
12.2 
Independent Ethics Committee / Institutional Review Board ................... 142 
12.3 
Informed consent ....................................................................................... 142 
12.4 
Compensation to subjects and investigators .............................................. 143 
12.5 
Protocol adherence/compliance ................................................................. 143 
12.6 
Protocol amendments ................................................................................ 144 
12.7 
Essential documents and retention of documents ...................................... 144 


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12.8 
Monitoring ................................................................................................. 145 
12.9 
Investigator Site File .................................................................................. 146 
12.10 
Audit .......................................................................................................... 146 
12.11 
Inspections ................................................................................................. 146 
12.12 
Reporting of study results and publication ................................................ 147 
13 REFERENCES ......................................................................................................... 148 
14 APPENDICES .......................................................................................................... 154 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule for subjects in the high-risk 
prevention group ....................................................................................... 81 
Table 2 
Visit and assessment schedule for subjects in the early treatment 
group (recruitment into this group was discontinued from protocol 
version 6 onwards) .................................................................................... 84 
Table 3 
Glasgow Coma Scale ................................................................................ 94 
Table 4 
Derivation of verbal score for intubated subjects ...................................... 95 
Table 5 
WFNS grade .............................................................................................. 96 
Table 6 
Abbreviated NIHSS ................................................................................... 99 
Table 7 
Analysis datasets usage ........................................................................... 127 
 
LIST OF FIGURES 
 
Figure 1 
Study design .............................................................................................. 50 
 
LIST OF APPENDICES 
 
Appendix 1 
Definition of “thick and diffuse clot” on hospital admission CT scan .... 154 
Appendix 2 
Global vasospasm assessment ................................................................. 156 
Appendix 3 
Patient Management Guidelines .............................................................. 158 
Appendix 4 
Glasgow Outcome Scale (extended version) and Modified Rankin 
Scale ........................................................................................................ 164 
Appendix 5 
Montreal Cognitive Assessment .............................................................. 171 
Appendix 6 
Stroke Specific Quality of Life ............................................................... 172 
Appendix 7 
EQ-5D (5L) ............................................................................................. 178 
Appendix 8 
Oxford Participation and Activities Questionnaire ................................. 180 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
aNIHSS  
Abbreviated National Institutes of Health Stroke Scale 
ARDS  
Acute respiratory distress syndrome 
aSAH  
Aneurysmal subarachnoid hemorrhage 
AST  
Aspartate aminotransferase 
AUC  
Area under the plasma concentration-time curve 
BP  
Blood pressure 
CEC  
Clinical Event Committee 
CFR  
Code of Federal Regulations (US) 
CI  
Confidence interval 
CL  
Confidence limits 
CMH  
Cochran-Mantel-Haenszel 
CNS  
Central nervous system 
COVID-19  
Coronavirus disease 2019 
CRA  
Clinical research associate 
CRO  
Contract Research Organization 
CT  
Computed tomography 
CTA  
Computed tomography angiogram/graphy 
CTT  
Clinical trial team 
CVP  
Central venous pressure 
DBP  
Diastolic blood pressure 
DCI  
Delayed cerebral ischemia 
DICOM  
Digital Imaging and Communications in Medicine 
DIND  
Delayed ischemic neurological deficit 
DSA  
Digital subtraction angiogram/graphy 


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ECG  
Electrocardiogram 
eCRF  
Electronic case report form 
EDC  
Electronic Data Capture 
EEG  
Electroencephalogram 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ERA  
Endothelin receptor antagonist 
ET  
Endothelin 
ETx  
Endovascular therapy 
EU  
European Union 
FAS  
Full analysis set 
FiO2  
Fraction of inspired oxygen 
GCP  
Good Clinical Practice 
GCS  
Glasgow Coma Scale 
GOSE  
Glasgow Outcome Scale – Extended 
HD  
Hemodynamic 
HR  
Heart rate 
i.v.  
Intravenous 
IAG  
Image Acquisition Guidelines 
IB  
Investigator’s Brochure 
ICA  
Internal carotid artery 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
ICP  
Intracranial pressure 
ICU  
Intensive care unit 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
IMP  
Investigational medicinal product 


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IRB  
Institutional Review Board 
IRC  
Independent Radiology Committee 
IRT  
Interactive response technology 
ISAC  
Independent statistical analysis center 
ISF  
Investigator Site File 
IVC  
Inferior vena cava 
IVH  
Intra-ventricular hemorrhage 
MAP  
Mean arterial pressure 
MedDRA  
Medical Dictionary for Regulatory Activities 
mGCS  
Modified Glasgow Coma Scale 
MoCA  
Montreal Cognitive Assessment 
MRI  
Magnetic resonance imaging 
mRS  
Modified Rankin Scale 
OATP  
Organic anion transporting polypeptide 
OR  
Odds ratio 
Ox-PAQ  
Oxford Participation and Activities Questionnaire 
PaCO2  
Partial pressure of carbon dioxide in arterial blood 
PaO2  
Partial pressure of oxygen in arterial blood 
PEEP  
Positive End Expiratory Pressure 
PI  
Principal investigator 
PPS  
Per-protocol analysis set 
QoL  
Quality of Life 
QS  
Quality System 
RR  
Relative risk 
RSI  
Reference safety information 
SAE  
Serious adverse event 
SAH  
Subarachnoid hemorrhage 
SaO2  
Arterial oxygen saturation 


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SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure 
SI  
Standardized International 
SIV  
Site initiation visit 
SOC  
System organ class 
SpO2  
Peripheral capillary oxygen saturation 
SS-QOL  
Stroke Specific Quality of Life 
SUSAR  
Suspected unexpected serious adverse reaction 
SVV  
Stroke volume variability 
TCD  
Transcranial Doppler 
TEAE  
Treatment-emergent adverse event 
US  
United States 
VAS  
Visual analog scale 
w/v  
Weight/volume 
WFNS  
World Federation of Neurological Societies 
WHO  
World Health Organization 
 
 


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SUBSTANTIAL GLOBAL AMENDMENT 6 
Amendment rationale 
This amendment applies to global protocol ID-054-304 Version 6 dated 29 April 2021. The 
resulting amended global protocol is Version 7 dated 18 February 2022. 
The purpose of this substantial amendment is to modify the definition of the main 
secondary efficacy endpoint and the hierarchical statistical testing strategy related to the 
other secondary endpoints.  
The main secondary endpoint definition was updated: in addition to the already existing 
all-cause infarcts ≥ 5 cm3 at Day 16 post-study drug initiation, clinically relevant infarcts 
< 5 cm3 have been added. The latter are defined as those new or worsened infarcts < 5 cm3 
that occur in subjects with CEC-adjudicated clinical deterioration due to DCI.  
Routine blinded monitoring of the event rate during the REACT study revealed a 
lower-than-expected incidence of infarcts ≥ 5 cm3 resulting in insufficient power to detect 
a treatment effect. This led to an expansion of the endpoint definition to include smaller 
but clinically relevant infarcts. 
Although the infarcts < 5 cm3 have a lower association with vasospasm and poor outcome, 
their vasospastic origin and their contribution to poor outcome cannot be excluded.  Further 
details concerning the rationale for this main secondary endpoint are included in 
Section 6.6.2.1. 
This amendment includes the initial definition of the main secondary endpoint, i.e., 
all-cause new or worsened infarcts ≥ 5 cm3 at Day 16 post-study drug initiation, as an 
exploratory endpoint. 
This revised definition of the main secondary endpoint has no impact on the evaluation of 
the primary efficacy endpoint. 
In addition, the modified Rankin Scale has been formally included in the statistical 
hierarchical testing strategy, just before the GOSE. Results from the Japanese Phase 3 
studies (AC-054-305 and 306) show that the mRS can slightly better discriminate the 
treatment effect of clazosentan on clinical outcome at Week 12 post-aSAH, compared to 
the GOSE. This suggests a better sensitivity of the mRS, despite the similarity of the two 
instruments. Indeed, the mRS has recently been recommended over the GOSE as the 
preferred scale for measuring the long-term clinical outcome in SAH by the international 
clinical experts of the SAH common data elements working group [Suarez 2019].    
Minor editorial changes have been made, including alignment with the latest protocol 
template, and typographical errors have been corrected. 


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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 amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis. 
2.2 
Secondary objectives 
3.1.2 
Study duration 
3.3.3 
Clinical Event Committee 
6.1.2 
Main secondary endpoint 
6.1.2.2 
Other secondary endpoints 
6.1.3.2 
Other efficacy endpoints 
6.6.2 
Rationale for the choice of secondary efficacy endpoints 
6.6.2.1 
Occurrence of clinically relevant cerebral infarction at Day 16 post-study drug 
initiation defined as: all-cause cerebral infarction ≥ 5 cm3 or cerebral infarction 
< 5 cm3 in subjects with clinical deterioration due to DCI 
6.6.2.2 
Modified Rankin Scale and Glasgow Outcome Scale Extended 
7.2.2.1.1 
Glasgow Coma Scale 
7.2.2.4.4 
Day 16 post-study drug initiation 
9.1.4 
Definition of suspected unexpected serious adverse reactions 
10.1.7 
Usage of the analysis sets 
10.2.2 
Secondary efficacy variables 
10.2.2.1 
Main secondary variables 
10.2.2.2 
Other secondary efficacy variable 
10.3.1 
Overall testing strategy 
10.3.2.3 
Handling of missing data 
10.3.3.1 
Occurrence of clinically relevant cerebral infarction at Day 16 post-study drug 
initiation defined as: all-cause cerebral infarction ≥ 5 cm3 or cerebral infarction 
< 5 cm3 in subjects with clinical deterioration due to DCI 


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10.3.3.2 
Clinical outcome as assessed by the mRS at Week 12 post-aSAH 
10.3.3.3 
Clinical outcome as assessed by the GOSE at Week 12 post-aSAH 
10.5.2 
Secondary efficacy objective (main) 
12.3 
Informed consent 
Appendix 2 
Global vasospasm assessment 
Summary of previous amendments 
Amendment Date 
Main reason(s) 
1 
18 June 2018 
Non-substantial amendment to address the applicable 
comments from those received on 3 May 2018 during 
the US FDA review for the Clinical Trial Application, 
and those received on 29 May 2018 during the 
Voluntary Harmonisation Procedure review for the 
Clinical Trial Application in the EU: 
• Extended the duration for the collection of serious 
adverse events from 30 days post-permanent 
study drug discontinuation until the End-of-Study 
visit. 
• Provided information regarding the potential 
pulmonary adverse events associated with the 
concomitant administration of nimodipine and 
clazosentan. 
• Clarified the main statistical analysis for the 
primary endpoint, the overall testing strategy, and 
the supportive analyses. 
2 
4 December 2018 Substantial amendment to align the protocol with the 
Investigator’s Brochure (IB) Version 14 which had 
been amended to address requests received from the 
US FDA on 30 October 2018, following their review 
of the IB Version 13:  
• Restrictions 
were 
made 
concerning 
the 
contraception and breastfeeding requirements by 
extending them from 24 hours to 30 days 
post-study drug discontinuation. 
• Clarification was provided on certain study 
procedures and entry criteria, new/revised 


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Amendment Date 
Main reason(s) 
exploratory endpoints were added, and other 
minor modifications were done. 
• Edits were implemented in the statistical methods 
section to align with the most recent version of the 
statistical analysis plan. 
3 
7 January 2020 
Substantial amendment to add a Quality of Life 
assessment at 24 weeks (6 months) post-aSAH. 
• 
The EQ-5D questionnaire was added at Week 24 
post-aSAH. 
• 
The End-of-Study (EOS) visit at the individual 
subject level has been rescheduled to Week 24 
post-aSAH and the previous EOS visit has been 
renamed ‘Week 12 visit’. 
• 
Serious adverse event (SAE) reporting was 
extended from up to 3 months to up to 6 months. 
• 
Clarification on supportive data collection for the 
primary endpoint has been provided. 
• 
The rules for rescue therapy usage have been 
clarified.  
4 
2 July 2020 
Substantial amendment to describe the follow-up and 
collection of data until Day 14 post-study drug 
initiation for subjects who are discharged from the 
study site prior to Day 14. 
• 
A follow-up visit/phone call was introduced for 
subjects who were discharged from the study site 
prior to Day 14 post-study drug initiation. The 
data to be collected and recorded during this 
follow-up were described. 
• 
It was explained how subjects who were 
discharged prior to Day 14 could meet the 
primary efficacy endpoint based on data 
collected between discharge and Day 14. 
• 
A separate dedicated section was added to 
describe the observation period for the primary 
endpoint. 


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Amendment Date 
Main reason(s) 
• 
Information concerning image archiving at the 
study sites was added. 
5 
29 April 2021 
Substantial amendment to discontinue recruitment 
into the Early Treatment (ET) group following a 
recommendation received by the study Independent 
Data Monitoring Committee (IDMC) on 2 April 
2021. 
The decision to discontinue the recruitment into the 
ET group was not based on a planned interim efficacy 
analysis, nor on urgent safety observations but a low 
rate of recruitment into this cohort since the outset of 
the study, making the contribution of these subjects 
to the overall study futile. 
 
 


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PROTOCOL SYNOPSIS ID-054-304 
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). 
ACRONYM 
REACT: pRevention and trEament of vAsospasm with 
ClazosenTan 
OBJECTIVES 
Primary objective 
• To determine the efficacy of clazosentan in preventing 
clinical deterioration due to DCI, in subjects with aSAH. 
Secondary objectives 
• To evaluate the effect of clazosentan on the occurrence of 
clinically relevant cerebral infarction at Day 16 post-study 
drug initiation. 
• To evaluate the effect of clazosentan on long-term clinical 
outcome, cognition, and health-related Quality of Life 
(QoL) at Week 12 and QoL at Week 24 post-aSAH. 
• To evaluate the safety and tolerability of clazosentan in the 
selected population up to 24 hours post-study drug 
discontinuation. 
Other objectives 
• To evaluate the effect of clazosentan on healthcare resource 
utilization. 
DESIGN 
This is a prospective, multi-center, double-blind, randomized, 
placebo-controlled, parallel-design, Phase 3 study. 
Subjects will be randomized 1:1 to clazosentan 15 mg/h or 
placebo, stratified by their World Federation of Neurological 
Societies (WFNS) grade at hospital admission (1–2 vs 3–5), 
patient population (high-risk prevention vs early treatment*), 
and age at hospital admission (≤ 60 and > 60 years).  
*Recruitment into the early treatment group was discontinued from 
protocol version 6 onwards. 


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Overall the study will enroll 400 subjects in 2 treatment 
arms; 200 subjects per arm. 
The study will be conducted in approximately 100 sites in 
approximately 15 countries. 
Once randomized, the subject will enter a double-blind 
treatment period of variable duration followed by a follow-up 
period terminating with an End-of-Study (EOS) visit at 
Week 24 post-aSAH see Section 3.1 for an overview of the 
study design.  
The study comprises the following consecutive periods: 
Screening period: Starts with the signature of the informed 
consent form and ends with subject randomization. During the 
screening period, the subject will be evaluated for suitability 
for the study based on the inclusion and exclusion criteria. 
Treatment period: Starts immediately with the baseline 
assessments followed by the initiation of study drug infusion 
and ends with the permanent discontinuation of study drug.  
Treatment duration is dependent on the subject’s individual 
clinical course and the investigator’s judgment on the 
perceived 
need 
to 
continue 
the 
study 
drug 
[see 
Section 5.1.3.3.4 for further details]. The maximum duration 
of treatment is 14 days. 
Observation period for the primary endpoint: This period 
covers the interval over which the subject may qualify for the 
primary endpoint of the study. It starts with the initiation of 
study drug infusion and ends on and includes Day 14 
post-study drug initiation irrespective of treatment duration. 
Subjects must not be discharged from the hospital earlier than 
Day 14 (and not prior to performing the 24-hour safety 
follow-up period). 
24-hour safety follow-up period: Starts with the permanent 
discontinuation of study drug and ends 24 hours later. Subjects 
must not be discharged from the hospital until the end of this 
period [see Section 7.1.3].  


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Extended follow-up period: Starts after the 24-hour safety 
follow-up period and ends with the EOS visit, occurring 
24 weeks after the aSAH [see Section 7.1.4]. 
EOS (individual subject): This is defined as the last visit 
performed for the study (i.e., the EOS visit, performed 
24 weeks after the aSAH), or the date of premature 
discontinuation 
from 
the 
study, 
if 
applicable 
[see Section 7.1.8].  
EOS (study level): This time point occurs when the last 
subject completes his/her EOS visit. 
PLANNED DURATION 
The study starts with the first subject, first visit and ends with 
the last subject, last visit. The study is expected to last 
approximately 47 months. 
The duration of participation in the study for an individual 
subject is expected to be approximately 6 months.  
SITES/COUNTRIES 
Approximately 100 sites in approximately 15 countries. 
INCLUSION CRITERIA 
1. Written informed consent* to participate in the study must 
be obtained from the subject or proxy/legal representative 
at any time from hospital admission to prior to initiation of 
any study-mandated procedure. 
*Consent will be obtained by a procedure that is based on local 
regulations and acceptable to local authorities (including, e.g., deferral 
of consent). The consent form must also be signed by the investigator 
or delegate prior to any study-mandated procedure. 
2. Males and females aged 18 to 70 years (inclusive, at 
hospital admission). 
3. Subjects 
with 
a 
ruptured 
saccular 
aneurysm, 
angiographically 
confirmed 
by 
digital 
subtraction 
angiogram (DSA) or computed tomography angiogram 
(CTA), which has been successfully secured* within 
72 hours of rupture by surgical clipping or endovascular 
coiling.** 
*A successfully secured aneurysm (clipping or coiling) is defined as 
> 80% exclusion by volume with < 50% narrowing of parent vessel or 
adjacent branches (assessed locally). In addition, ‘successful’ implies 
no additional intervention planned on the repaired aneurysm in the 
3-month period following the initial procedure. 


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**The aneurysm may have been secured by both clipping and coiling. 
Stent-assisted coiling and other endovascular devices (e.g., Web® 
device) are not allowed. The temporary use of approved devices during 
the coiling procedure is allowed, provided their use does not require 
anti-platelet or other agents affecting clotting 
mechanisms. 
Determination of date/time of aneurysm rupture is described in 
Section 7.2.1.1. 
4. WFNS grades 1–4 (based on Glasgow Coma Scale [GCS]) 
assessed after recovery from the aneurysm-securing 
procedure and after external ventricular drainage for 
hydrocephalus, if required. 
5. High-risk prevention: Subjects with a “thick and diffuse 
clot”* on the hospital admission computed tomography 
(CT) scan, absence of cerebral vasospasm at the time of 
randomization, and possibility to start study drug in the 
intensive care unit (ICU; or equivalent environment where 
all protocol assessments can be performed and the Patient 
Management Guidelines followed), within 96 hours 
following the time of the aneurysm rupture. 
*Thick and diffuse is defined as a thick confluent clot, more than 4 mm 
in thickness, involving 3 or more basal cisterns. See Appendix 1 for 
further details. 
6. A) Presence of a cerebral CT scan, performed at least 
8 hours post-aneurysm-securing procedure and within 
24 hours prior to randomization.  
6. B) Absence of a significant (e.g., symptomatic or large) 
new or worsened* cerebral infarct or re-bleeding of the 
repaired aneurysm on the post-procedure CT scan. 
*This CT scan will be compared with the admission and any routinely 
performed post-procedure CT scan(s) to detect new or worsened 
infarcts and re-bleeding which appear after the aneurysm-securing 
procedure.  
7. A woman of childbearing potential [see definition in 
Section 4.5] is eligible only if the serum pregnancy test 
performed during the screening period is negative. 
Agreement must be obtained to take the necessary 
precautions to avoid pregnancy from hospital discharge 
until 30 days post-study drug discontinuation [see 
Section 4.7]. 


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If breastfeeding, agreement must be obtained to refrain for 
the duration of the treatment with study drug and until 
30 days post-study drug discontinuation.  
8. Males are eligible for study participation only if they agree 
to take the necessary precautions to avoid pregnancy in a 
female partner from hospital discharge until 30 days 
post-study drug discontinuation [see Section 4.8]. 
EXCLUSION CRITERIA 
aSAH, aneurysm-securing procedure, vasospasm: 
1. Subjects with subarachnoid hemorrhage (SAH) due to 
causes other than a saccular aneurysm (e.g., trauma or 
rupture of fusiform or mycotic aneurysms, SAH associated 
with arterio-venous malformation, vertebral dissections). 
2. Subjects with at least one unruptured aneurysm for whom 
a subsequent intervention is planned within 3 months of the 
aSAH.  
3. Significant bleeding post aneurysm-securing procedure 
(e.g., due to intra-ventricular drain, intra-cerebral 
hemorrhage, epidural hematoma, vessel dissection or 
rupture, re-bleeding of the repaired aneurysm*), based on 
investigator judgment.  
*Re-bleeding prior to the aneurysm-securing procedure is not an 
exclusion criterion. 
4. Intra- or peri-aneurysm securing procedure complication 
requiring non-routine medical or interventional treatment 
such as administration of an antithrombotic or anti-platelet 
agent (e.g., abciximab), which is not completely resolved 
prior to randomization.  
5. Intra-ventricular hemorrhage on the hospital admission CT 
scan, filling more than 50% of both lateral ventricles and 
with involvement of the 3rd and 4th ventricles. 
6. Intra-cerebral hemorrhage on the hospital admission CT 
scan, with an approximate volume of > 50 mL. 


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7. Presence of cerebral vasospasm at hospital admission 
(initial admission or transfer from another hospital) 
believed to be associated with a prior bleed (i.e., occurring 
before the bleed for which the subject is currently 
hospitalized). 
Vasospasm 
occurring 
during 
the 
aneurysm-securing procedure is not an exclusion criterion. 
Neurological and functional status: 
8. Subjects with a new major neurological deficit occurring 
post aneurysm-securing procedure* which is attributable to 
the procedure and does not improve to pre-procedure status 
before randomization. 
*Evaluation for a new major neurological deficit post procedure 
implies the reversal of sedation (or waiting for the subject to recover 
from sedation) and the performance of a neurological examination. 
9. Subjects 
who 
are 
still 
under 
the 
influence 
of 
pharmacological sedation at the time of randomization or 
who are, for whatever reason, not evaluable for baseline 
and regular daily neurological assessments. 
10. WFNS grade 5 (based on GCS) immediately prior to 
planned randomization, assessed after external ventricular 
drainage for hydrocephalus, if required. 
11. Subjects with a GCS score of ≤ 9 at the time of 
randomization and without intracranial pressure (ICP) 
monitoring. 
12. Modified Rankin Scale (mRS) score of 3 or higher, prior to 
the aSAH (i.e., due to a chronic condition). 
Other clinical considerations: 
13. Subjects with total bilirubin > 2 × the upper limit of normal, 
and/or a known diagnosis or clinical suspicion of liver 
cirrhosis or moderate to severe hepatic impairment. 
14. Any concomitant condition or disease (including 
psychiatric and neurological conditions, drug abuse, severe 
alcoholism) which, in the opinion of the investigator, 
would affect the assessment of the safety or efficacy of the 
study treatment. 


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15. Hypotension (systolic blood pressure ≤ 90 mmHg) at time 
of randomization that is refractory to treatment. 
16. Unresolved pulmonary edema or significant pneumonia 
still present at the time of randomization, or severe hypoxia 
at the time of randomization in intubated subjects, defined 
as PaO2/FiO2 ≤ 200. 
17. High sustained ICP (> 25 mmHg lasting > 20 minutes) at 
time of randomization, despite optimal treatment, in 
subjects with ICP monitoring. 
18. Severe cardiac failure requiring inotropic support at the 
time of randomization. 
Medications and therapies: 
19. Lumbar and/or cisternal drainage performed specifically to 
prevent or treat cerebral vasospasm at any time from 
hospital admission to randomization.  
20. Prophylactic or therapeutic administration of intra-arterial 
vasodilators* or ozagrel, or performance of cerebral 
angioplasty** at any time from hospital admission to 
randomization. 
*Mechanically induced vasospasm occurring during the aneurysm-
securing procedure may be treated with local administration of 
vasodilators (e.g., intra-arterial, topical). 
**Balloon assisted vascular remodeling during the aneurysm-coiling 
procedure is permitted. 
21. Subjects for whom at the time of randomization 
administration of urgent rescue therapy (i.e., cerebral 
angioplasty, 
intra-arterial/intrathecal/intra-cisternal/ 
intra-ventricular administration of vasodilators or ozagrel) 
is anticipated. 
22. Use of intrathecal, intra-cisternal, or intra-ventricular* 
thrombolytics at any time from hospital admission to 
randomization.  
*Use of thrombolytics to open an occluded drain is permitted. 


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23. Administration 
of 
intrathecal, 
intra-cisternal, 
and 
intra-ventricular 
vasodilators 
(e.g., 
nimodipine), 
intravenous (i.v.) nicardipine (except for blood pressure 
control), or i.v. milrinone*, within 4 hours prior to 
randomization. 
*Administration of i.v. milrinone at any time from hospital admission 
to randomization is exclusionary if used to prevent or treat cerebral 
vasospasm. 
24. Administration of i.v. fasudil or i.v. ozagrel within 24 hours 
prior to randomization. 
25. Use of intra-aortic balloon counter-pulsation devices at any 
time from hospital admission to randomization. 
26. Use at any time from hospital admission to randomization, 
of any investigational drugs, procedures or devices, 
including:  
• investigational clipping material and investigational 
coiling material such as liquid embolic material, stents or 
flow diverting devices, and,  
• any other medication administered to prevent or treat 
vasospasm, reduce ischemic complications, or to improve 
clinical outcome post-aSAH, that has not been approved 
for these specific indications by local health authorities 
(e.g., new post-hospital admission prescription of “statins”, 
therapeutic hypothermia). 
27. Subjects receiving strong inhibitors of organic anion 
transporting polypeptide (OATP)1B1 and OATP1B3 
transporter proteins (e.g., cyclosporin A, rifampicin, 
lopinavir/ritonavir), or subjects for whom it is likely at the 
time of randomization that these medications will be started 
during the study treatment infusion period. 
28. Known hypersensitivity to clazosentan or any excipient in 
the formulation. 


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STUDY TREATMENTS 
Clazosentan is supplied in clear glass vials as a concentrated 
solution for continuous i.v. administration, after dilution.  
Each vial contains 150 mg of clazosentan in a total volume of 
6 mL, providing a concentration of 25 mg/mL (2.5% w/v, pH 
8.0 ± 0.1). Each vial contains a small volume of overfill. 
Matching placebo is supplied in identical clear glass vials with 
the same formulation as described above (excluding 
clazosentan) and the same volume. 
Subjects will be administered either clazosentan, as a 
continuous i.v. infusion at the dose of 15 mg/h, or placebo at 
the same corresponding infusion rate [see Section 5.1.3.3.2]. 
For subjects enrolled in the high-risk prevention group, 
treatment will be administered, where possible, for 14 days. 
For subjects that require early discharge from the ICU (or 
equivalent), study drug must be administered for a minimum 
of 10 days. This duration covers the period when vasospasm is 
most likely to occur. 
For subjects randomized in the early treatment group*, 
treatment will be administered for a minimum of 6 days and a 
maximum of 14 days. 
Study treatment must be discontinued if one of the 
study-treatment stopping criteria is met see Section 5.1.3.4.1]. 
*Recruitment into the early treatment group was discontinued from 
protocol version 6 onwards. 
CONCOMITANT 
THERAPY 
Allowed concomitant therapy 
Local standard of care 
The usual standard of care for the management of aSAH is 
allowed until the primary endpoint assessment at 14 days 
post-study drug initiation, except for those therapies listed in 
the “forbidden concomitant medication” section and must be 
documented in the medical charts.  
Nimodipine (oral or i.v.) may be administered for the usual 
duration if it is routine standard of care at the site. 


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“Statins” (e.g., simvastatin, pravastatin) may only be 
administered if the subject was receiving them chronically for 
the treatment of high cholesterol levels. 
Vaccines 
(including 
those 
for 
COVID-19) 
may 
be 
administered at any time during the study.   
Rescue therapy 
For the purpose of this study, rescue therapy refers to the 
escalation of medical therapy beyond standard hemodynamic 
therapy, for the treatment of refractory vasospasm. Refractory 
vasospasm is characterized by a minimum of 2-points 
worsening on either of the neurological scales and no response 
to HD therapy. The following therapies are considered rescue 
therapies:  
• balloon angioplasty,  
• intra-arterial, 
intrathecal/intra-cisternal/intra-ventricular 
administration of vasodilators or ozagrel. 
The decision to administer the above rescue therapies is based 
on local standard of care and is allowed at any time during the 
study for refractory vasospasm. The refractory nature is to be 
documented in the electronic case report form (eCRF). 
Intravenous administration of vasodilators (e.g., nicardipine, 
milrinone) is allowed as rescue therapy only if preceded by 
intra-arterial administration of a vasodilator.  
The other medications in the “forbidden concomitant therapy” 
section below (with their respective routes of administration), 
are not considered as rescue therapies and their administration 
is forbidden until Day 14 post-study drug initiation. 
Study drug must be temporarily interrupted prior to any rescue 
therapy and must be resumed after the completion of the 
therapy. 
Forbidden concomitant therapy 
The following medications/therapies are forbidden until the 
primary endpoint assessment at Day 14 post-study drug 
initiation, due to their potential to interfere with the evaluation 
of efficacy or safety, or due to the potential for a drug-drug 


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interaction with study drug (refer to the Investigator’s 
Brochure for more information). Those that are described 
above under “rescue therapy” are permitted in the treatment of 
refractory vasospasm, but are forbidden otherwise. 
• Intra-aortic balloon device. 
• Lumbar and/or cisternal drainage for the prevention of 
cerebral vasospasm / DCI.  
• Milrinone 
i.v., 
nicardipine 
i.v.*, 
and 
intrathecal/ 
intra-cisternal/intra-ventricular 
vasodilators 
(e.g., 
nimodipine), must be discontinued at least 4 hours prior to 
enrollment.  
*Administration of i.v. milrinone at any time from hospital 
admission to randomization is exclusionary if used to 
prevent or treat cerebral vasospasm. Nicardipine i.v. may 
be used at any time for blood pressure control. 
• Magnesium i.v., albumin i.v., or plasma volume expander 
if administered specifically for the prevention of cerebral 
vasospasm and/or DCI. 
• Thrombolytics (including intrathecal, intra-cisternal, and 
intra-ventricular, administration) and antifibrinolytics 
(e.g., tranexamic acid). Use of thrombolytics to open an 
occluded drain is permitted. 
• Hypertonic saline i.v., if administered in the absence of 
hyponatremia, brain edema, or high ICP. 
• Mannitol i.v., if administered in the absence of brain edema 
or high ICP. 
• Strong inhibitors of OATP1B1 and OATP1B3 transporter 
proteins 
(e.g., 
cyclosporin 
A, 
rifampicin, 
lopinavir/ritonavir). 
• Other endothelin receptor antagonists (ERAs). 
• Any investigational drugs, procedures, or devices, 
including any other medication administered to treat 
cerebral vasospasm that has not been approved for this 
specific indication by local health authorities (e.g., 
therapeutic hypothermia, “statins”). 


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• Traditional 
medicines 
(i.e., 
plant-, 
animal-, 
or 
mineral-based medicine, such as traditional Chinese 
medicine). 
Study treatment must be permanently discontinued if one of 
the following is initiated during the treatment period: 
• Another ERA. 
• Another investigational product/procedure. 
• A strong inhibitor of OATP1B1 and OATP1B3 transporter 
proteins 
(e.g., 
cyclosporin 
A, 
rifampicin, 
lopinavir/ritonavir). 
ENDPOINTS 
Primary efficacy endpoint 
The primary efficacy endpoint is the occurrence of clinical 
deterioration due to DCI from study drug initiation up to 
14 days post-study drug initiation. 
Clinical deterioration due to DCI is defined as a worsening of 
at least 2 points compared to the reference score, on the mGCS 
or the aNIHSS, lasting for at least 2 hours, which cannot be 
entirely attributed to causes other than cerebral vasospasm. It 
is centrally adjudicated by the Clinical Event Committee 
(CEC) based on a written charter and review of clinical data, 
case narratives, angiograms, and CT scans.  
Secondary efficacy endpoints 
• Main secondary endpoint: The occurrence of clinically 
relevant cerebral infarction* at Day 16 post-study drug 
initiation defined as: 
  
− all-cause cerebral infarction ≥ 5 cm3 or  
− cerebral infarction < 5 cm3 in subjects with clinical 
deterioration due to DCI  
* Cerebral infarction refers to new or worsened infarcts and is determined 
by central radiology review, comparing the total volume of infarcts on the 
CT scan performed 16 days after study drug initiation with the total volume 
on the CT scan performed just prior to randomization. If the CT scan cannot 
be performed on Day 16, then it is acceptable for the CT to be performed 
within 7 days following Day 16. If a subject is discharged from the hospital 
prior to Day 16, the CT scan is performed on the day of hospital discharge. 
Clinical deterioration due to DCI and cerebral infarctions ≥ 5 cm3 are 


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confirmed by the CEC. Cerebral infarctions < 5 cm3 in subjects with clinical 
deterioration due to DCI are derived from both the CEC data (primary 
endpoint) and the IRC data (for infarct size). 
Other secondary endpoints:  
• Long-term clinical outcome assessed by the mRS at 
Week 12 post-aSAH, dichotomized into poor outcome 
(score ≥ 3) and good outcome (score < 3). 
• Long-term clinical outcome assessed by the Glasgow 
Outcome Scale Extended (GOSE) at Week 12 post-aSAH, 
dichotomized into poor outcome (score ≤ 4) and good 
outcome (score > 4). 
Exploratory efficacy endpoints 
Exploratory efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
• Occurrence of treatment-emergent adverse events (TEAEs) 
up to 24 hours after study drug discontinuation. 
• Occurrence of serious TEAEs up to 24 hours after study 
drug discontinuation.  
• Occurrence of TEAEs leading to premature discontinuation 
of study drug. 
• Occurrence of death (all causes) up to Week 24 post-aSAH. 
• Occurrence of TEAEs of specific interest (i.e., lung 
complications, hypotension, anemia, cerebral hemorrhage, 
cerebral edema, fluid retention, hepatic disorders, 
tachyarrhythmia) up to 24 hours after study drug 
discontinuation. 
• Occurrence of rescue therapy-specific adverse events up to 
hospital discharge (or Week 12, whichever is earlier). 
• Occurrence of treatment-emergent marked laboratory 
abnormalities 
up 
to 
24 
hours 
after 
study 
drug 
discontinuation, and changes from baseline to end of study 
drug administration for selected centrally assessed 
laboratory parameters. 


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Other endpoints 
Other endpoints are described in Sections 6.1.3, 6.3, 6.4, and 
6.5.  
ASSESSMENTS 
Refer to the schedule of assessments in Table 1 and Table 2.  
STATISTICAL 
METHODOLOGY 
Analysis sets 
Screened analysis set 
The Screened analysis set includes all subjects who have given 
informed consent to participate in the study and have a subject 
identification number.  
Randomized analysis set 
The Randomized analysis set includes all subjects who have 
been assigned to a study treatment. 
Full analysis set 
The Full analysis set (FAS) includes all subjects from the 
Randomized analysis set who have started the study treatment. 
Per-protocol analysis set 
The Per-protocol analysis set (PPS) comprises all subjects 
from the FAS who sufficiently complied with the protocol to 
be likely to exhibit the treatment effects. 
Safety analysis set 
The Safety analysis set includes all subjects who started study 
drug (as recorded in the eCRF).  
Statistical hypotheses 
Four null hypotheses will be tested according to a 
fixed-sequence procedure, at the two-sided significance level 
of 0.05 until first non-rejection.  
The first null hypothesis is that there is no difference between 
clazosentan 15 mg/h and placebo in the occurrence of clinical 
deterioration due to DCI from study drug initiation up to 


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14 days post-study drug initiation. This hypothesis will be 
tested at a two-sided significance level of 0.05. 
The second null hypothesis is that there is no difference 
between clazosentan 15 mg/h and placebo in the occurrence of 
clinically relevant cerebral infarction at Day 16 post-study 
drug initiation defined as: 
• all-cause cerebral infarction ≥ 5 cm3 or  
• cerebral infarction < 5 cm3 in subjects with clinical 
deterioration due to DCI.  
This hypothesis will be tested at a two-sided significance level 
of 0.05. 
The third null hypothesis is that there is no difference between 
clazosentan 15 mg/h and placebo in the proportions of subjects 
with a poor mRS score at Week 12 post-aSAH. This hypothesis 
will be tested at a two-sided significance level of 0.05. 
The fourth null hypothesis is that there is no difference 
between clazosentan 15 mg/h and placebo in the proportions of 
subjects with a poor GOSE score at Week 12 post-aSAH. This 
hypothesis will be tested at a two-sided significance level of 
0.05. 
Analysis of the primary efficacy variable 
The primary statistical analysis will be performed on the FAS, 
according to the intent-to-treat approach. 
The null hypothesis (H0) is that the occurrence of clinical 
deterioration due to DCI in subjects treated with clazosentan 
15 mg/h is not different from placebo. The alternative 
hypothesis (HA) is that the event rate in the clazosentan 
15 mg/h arm differs from the placebo arm. 
The 
null 
hypothesis 
will 
be 
tested 
using 
a 
Cochran-Mantel-Haenszel test, stratified* on WFNS grade  
(1–2 vs 3–5) and age at hospital admission (≤ 60 and 
> 60 years), at the two-sided significance level of alpha = 0.05.  
Sensitivity analyses include repetition of the primary analysis 
on the PPS. 


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Supportive analyses include logistic regression to estimate 
treatment effect adjusting for hospital admission WFNS grade 
(1–2 vs 3–5) at time of randomization and age at hospital 
admission (≤ 60 and > 60 years). 
The primary efficacy analysis planned in protocols up to 
version 5 will be performed as a supplementary analysis: i.e., 
the primary efficacy analysis described in Section 10.3.2.2 will 
be repeated including the patient population (high-risk 
prevention vs early treatment) as an additional adjustment 
factor. 
*Recruitment into the early treatment group was discontinued from 
protocol version 6 onwards. Due to the low number of subjects randomized 
in this stratum this variable will not be used as an adjustment variable and 
will be excluded from interaction testing and subgroup analyses. 
Analysis of the secondary efficacy variables 
The proportion of subjects with a clinically relevant cerebral 
infarction at Day 16 post-study drug initiation and the 
proportion of subjects with poor clinical outcome (mRS and 
GOSE) at Week 12 post-aSAH will be analyzed in a similar 
manner as for the primary efficacy endpoint. 
Safety analysis 
Summaries of safety will be essentially reflected by descriptive 
statistics for each treatment arm.  
Analysis of other endpoints 
Treatment effects on the other endpoints will be evaluated and 
described in detail in the Statistical Analysis Plan. 
Subgroup analysis 
Subgroup analyses for the primary and the secondary 
endpoints will be conducted for WFNS grade and age at 
hospital admission*, factors identified with a statistically 
significant treatment × factor interaction, and subgroups 
described in Section 10.3.2.6. 
*Recruitment into the early treatment group was discontinued from 
protocol version 6 onwards. Due to the low number of subjects randomized 


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in this stratum this variable will not be used as an adjustment variable and 
will be excluded from interaction testing and subgroup analyses. 
Sample size 
Under the assumption that the true incidence of clinical 
deterioration due to DCI up to Day 14 post-study drug 
initiation in the placebo arm is 28% and in the clazosentan arm 
is 14%, a sample size of n = 176 in each treatment arm will 
have 90% power to show the superiority in response of 
clazosentan compared to placebo using Pearson’s ² test with 
a 5% two-sided significance level. When taking an 
approximate 10% drop-out rate into account, 400 subjects have 
to be enrolled in the study, with n = 200 randomized to each 
treatment arm.  
STUDY COMMITTEES 
Independent Data Monitoring Committee  
An Independent Data Monitoring Committee (IDMC) will 
have overall responsibility for safeguarding the interests of 
subjects by monitoring unblinded safety and efficacy data 
obtained in the study at regular intervals during 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 is empowered to recommend modifications to the 
protocol 
or 
premature 
study 
discontinuation, 
to 
enhance/preserve subject safety. 
The composition and operation of the IDMC is described in an 
IDMC charter. 
An Independent Statistical Analysis Center, not otherwise 
involved with study conduct, will perform the analyses and 
generate unblinded analysis reports for the regular safety 
analyses, exclusively for review by the IDMC.  
Independent Radiology Committee 
The Independent Radiology Committee (IRC) is composed of 
radiologists who are independent from the study/sponsor and 
blinded to treatment allocation.  


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The radiologists will retrospectively review the angiograms 
and CT scans submitted for each randomized subject to 
confirm: 
• the presence of common findings and clot size on the 
hospital admission CT scan, 
• the absence of exclusionary CT findings on the 
pre-randomization CT scan, 
• the presence and severity of cerebral vasospasm on the 
baseline angiograms (pre-randomization, for subjects 
randomized into the early treatment group*) and 
post-baseline angiograms (for all subjects, after study drug 
initiation), 
*Recruitment into the early treatment group was discontinued from 
protocol version 6 onwards. 
• the presence, location, and volume of new and worsened 
cerebral infarcts at Day 16 post-study drug initiation. 
The composition and operation of the IRC is described in an 
IRC charter. 
Clinical Event Committee 
The CEC is composed of clinicians with expertise in aSAH and 
who are blinded to treatment allocation.  
The committee will determine whether the primary endpoint 
and the first component of the main secondary endpoint 
(infarcts ≥ 5 cm3) have been met.  
The clinicians will review clinical and imaging data from all 
subjects to determine which cases fulfill the definition of the 
primary efficacy endpoint. They will also adjudicate cases for 
the presence of a new or worsened cerebral infarct ≥ 5 cm3, 
based on the central review of CT scans performed by the IRC 
or other available data when the Day 16 CT scan is missing. 
The composition, operation, and adjudication rules of the CEC 
is described in a CEC charter. 
 
 
 


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PROTOCOL 
1 
BACKGROUND 
1.1 Subarachnoid hemorrhage 
With an estimated overall incidence of 9 in 100,000 people worldwide [Connolly 2012, 
Stiener 2013] aneurysmal subarachnoid hemorrhage (aSAH) is an orphan disease and has 
a poor prognosis. Even after successful securing of the aneurysm with surgical clipping or 
endovascular coiling, patients remain at risk of developing cerebral vasospasm and delayed 
cerebral ischemia (DCI), which can result in neurological deficits and death 
[Connolly 2012, Stiener 2013]. Cerebral vasospasm develops in about two-thirds of aSAH 
patients, occurs most frequently between Days 4 and 10 post-aSAH, and rarely develops 
beyond 2 weeks after the aneurysm rupture. In 20–40% of aSAH patients, cerebral 
vasospasm results in clinical deterioration due to DCI [Bauer 2014]. The potential 
consequences of DCI include cerebral infarction, poor functional outcome, and mortality 
[Lanzino 1999a, Lanzino 1999b, Nolan 2006, Brilstra 2000, Roos 2000, Fergusen 2007, 
Rabinstein 2003]. An increasing number of patients survive aSAH today, and functional 
aspects of the clinical outcome, including neuropsychological deficits, become 
increasingly important. DCI has recently been identified to be the most important predictor 
of neuropsychological deficits [Stienen 2014]. 
1.2 Medical management of aSAH and its vasospastic complications 
Initial treatment of aSAH consists of securing the aneurysm with either a surgical clip or 
an endovascular coil to avoid re-bleeding, followed by a treatment protocol that keeps the 
patient well hydrated and blood pressure (BP) sufficiently high to ensure cerebral perfusion 
[Connolly 2012, Stiener 2013]. 
The only currently approved drug worldwide for the prevention of DCI is the calcium 
channel blocker nimodipine, which is standard of care in most centers in the US and the 
EU [Connolly 2012, Stiener 2013]. Nimodipine has been shown to improve neurological 
outcomes [Neil-Dwyer 1987, Pickard 1989]. Fasudil, a Rho-kinase inhibitor, ozagrel, a 
thromboxane A2 antagonist, and alprostadil, a phosphodiesterase inhibitor have been 
approved for the prevention or treatment of vasospasm in some Asian countries.  
As vasospasm is a major complication post-aSAH, the acute period following the 
aneurysm-securing procedure is accompanied by close monitoring of the patient’s 
neurological status, and routine monitoring may include transcranial Doppler (TCD), 
computed tomography angiography (CTA), computed tomography (CT) perfusion, or 
digital subtraction angiography (DSA). Modification in the TCD signal, or the visualization 
of vasospasm on angiography will trigger an intensification of the patient monitoring and 
if clinically indicated the start of hemodynamic (HD) therapy to increase the cerebral 
perfusion pressure.  


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HD therapy, consisting of the administration of fluids and vasopressors, is the first step in 
the treatment of symptoms of vasospasm. For aSAH patients who fail to respond to HD 
therapy, the only remaining treatment option currently available for reversal of cerebral 
vasospasm is endovascular therapy (ETx), an invasive procedure consisting of balloon 
angioplasty and/or intra-arterial administration of vasodilators. The use of ETx is 
recommended by scientific society guidelines, although no prospective randomized trials 
to prove its effectiveness have been performed [Connolly 2012]. 
1.3 Unmet medical need in aSAH 
Although nimodipine has been approved in the aSAH indication to prevent secondary 
ischemic complications of aSAH, it has not shown a consistent effect on angiographic 
cerebral vasospasm [Allen 1983, Petruk 1988].  
In uncontrolled studies ETx has shown an immediate effect on angiographic vasospasm. 
While technical success is achieved in the majority of balloon angioplasty procedures, 
clinical success rates vary considerably, with reversal of DCI observed in 31–77% of 
patients. Durability of the effect is relatively poor, and repeated procedures are often 
required [Abruzzo 2012, Hoh 2005]. ETx is associated with significant risks for the patient 
(up to 5% serious complications such as thrombosis, vessel rupture or dissection for each 
intravascular intervention). Furthermore, ETx is not widely available, and mainly limited 
to expert centers [Kaufmann 2007, Hoh 2005, Hayashi 2014]. 
Therefore, there is a high medical need for improved treatment options for aSAH following 
initial surgery or endovascular coiling, as an add-on therapy to nimodipine, to avoid 
progression to symptomatic vasospasm with its neurological complications and the use of 
HD or ETx. 
1.4 Clazosentan 
1.4.1 Mechanism of action 
Clazosentan is a highly specific endothelin (ET) receptor antagonist (ERA) with markedly 
higher binding affinity to the ETA than to the ETB subtype of ET receptors. It has 
vasodilatory properties on brain vessels and moderate systemic vasodilatory effects (refer 
to the Investigator’s Brochure [IB] for further details [Clazosentan IB]). In both nonclinical 
and clinical settings, it has been demonstrated that clazosentan consistently prevents the 
occurrence of vasospasm post-aSAH. In a recent exploratory clinical study (REVERSE), 
clazosentan showed some pharmacological effect on large vasospastic brain vessels as 
early as 3 hours post-study drug initiation, suggesting that clazosentan may be beneficial 
in early treatment of vasospasm post-aSAH [Clazosentan IB]. 


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1.4.2 Nonclinical summary 
Cerebral vasospasm post-aSAH is principally due to a reaction to extravasated blood from 
aneurysmal rupture. Increased levels of the potent vasoconstrictor ET are triggered by both 
oxyhemoglobin-induced ET production [Cosentino 1994] and direct release of ET from 
lysed red blood cells [Tippler 1994], and increased ET levels correlate with the 
development of cerebral vasospasm [Seifert 1995]. In nonclinical models of subarachnoid 
hemorrhage (SAH), ERAs have been shown to prevent or reverse cerebral vasospasm 
[Clozel 1993, Roux 1995], with minimal effect on the systemic circulation [Roux 1995].  
Prevention of cerebral vasospasm following experimental SAH was tested in dog and 
rabbit models of SAH [Roux 1997]. These studies showed that clazosentan could 
dose-dependently both prevent and reverse experimental cerebral vasospasm [Roux 1997]. 
Whereas clazosentan did not significantly affect the mean arterial pressure (MAP) or heart 
rate (HR) in rabbits, it did moderately decrease MAP in dogs by –17 ± 7% at 2 h after the 
highest infusion dose of 3 mg/kg/h. 
More detailed information can be found in the IB [Clazosentan IB]. 
1.4.3 Clinical summary 
Seven double-blind placebo-controlled clinical trials (three Phase 2, and four Phase 3) and 
one Phase 2 open-label study have been performed in subjects with aSAH to evaluate the 
safety and efficacy of clazosentan for prevention or treatment of cerebral vasospasm. These 
studies, which included over 1800 clazosentan-treated subjects, consistently showed a 
decreased incidence and severity of cerebral vasospasm in the clazosentan arms. Detailed 
study results are included in the clazosentan IB and summarized below. The most recent 
exploratory study investigated the potential of clazosentan to reverse established cerebral 
vasospasm [Clazosentan IB]. 
The initial Phase 2a study, AXV-034-2S01, reported a statistically significant reduction in 
the incidence and severity of angiographic cerebral vasospasm in subjects treated with 
clazosentan compared to placebo [Vajkoczy 2005]. In addition, this study included an 
exploratory part, in which the potential for clazosentan to reverse established cerebral 
vasospasm was shown in a limited number of subjects.  
In the subsequent Phase 2b dose-finding study, AC-054-201/CONSCIOUS-1, a 
statistically significant dose-related decrease in the incidence of moderate or severe 
cerebral vasospasm post-aSAH was shown at all tested clazosentan doses (1 mg/h, 5 mg/h, 
and 15 mg/h) vs placebo [Macdonald 2008]. 
A similar Phase 2b study conducted in Japan and South Korea, AC-054-202, confirmed 
the decrease in the incidence of moderate or severe angiographic cerebral vasospasm up to 
14 days post-aSAH using clazosentan at the doses of 5 mg/h and 10 mg/h [Fujimura 2017]. 


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The results of CONSCIOUS-1 prompted two Phase 3 studies with very similar design, 
AC-054-301/CONSCIOUS-2 [Macdonald 2011] and AC-054-302/CONSCIOUS-3 
[Macdonald 2012]. While CONSCIOUS-2 included aSAH subjects with aneurysm 
securing by surgical clipping, CONSCIOUS-3 included aSAH subjects post-endovascular 
coiling of the aneurysm. Both studies compared a 5 mg/h clazosentan dose to placebo and 
the CONSCIOUS-3 study also included a treatment arm with 15 mg/h clazosentan. The 
primary endpoint of both studies was the incidence of cerebral vasospasm-related 
morbidity and all-cause mortality 6 weeks post-aSAH. In CONSCIOUS-2, clazosentan at 
a dose of 5 mg/h showed a non-significant odds ratio (clazosentan:placebo) of 0.783 (95% 
confidence limits [CL]: 0.583–1.051; P = 0.1037) for mortality and vasospasm-related 
morbidity within 6 weeks post-aSAH. The CONSCIOUS-3 study was prematurely 
terminated due to the inconclusive results from CONSCIOUS-2. Exploratory analysis 
showed a non-significant odds ratio of 0.786 (95% CL: 0.479–1.289; P = 0.3395) in the 
5 mg/h group compared to placebo for mortality and vasospasm-related morbidity within 
6 weeks post-aSAH. With the 15 mg/h dose, the treatment effect of clazosentan compared 
to placebo was nominally statistically significant with an odds ratio of 0.474 (95% CL: 
0.275–0.818; P = 0.0073). No significant effect was observed on the 3-month Glasgow 
Outcome Scale Extended (GOSE) in any of the studies conducted. 
The two Phase 3 studies also showed reductions in the use of HD therapy and ETx in 
clazosentan-treated subjects compared to placebo. In CONSCIOUS-2, clazosentan 5 mg/h 
reduced the use of rescue therapy, including ETx, by 36% (95% CL: 14–53%). In 
CONSCIOUS-3, clazosentan at the dose of 15 mg/h reduced the use of rescue therapy, 
including ETx, by 65% (95% CL: 38–80%), and the incidence of delayed ischemic 
neurological deficits (DINDs) by 54% (95% CL: 22–72%) compared to placebo. 
The REVERSE study (AC-054-203; open-label pilot Phase 2 study), which enrolled a 
limited number of subjects (n = 14), showed that while clazosentan is able to reverse 
established vasospasm within 3 hours in some cases, this effect was not pronounced enough 
in other cases to an extent that ETx could be avoided. However, this study showed a clear 
pharmacological effect of clazosentan on both large and distal vessels suggesting that when 
administered early enough, clazosentan could have the potential to reverse established 
moderate vasospasm. 
Two Phase 3 studies with identical designs and endpoints were conducted in Japan. 
AC-054-305 included aSAH subjects with their aneurysm secured by endovascular coiling 
and AC-054-306 included aSAH subjects after surgical clipping of the aneurysm. Both 
studies compared clazosentan at the dose of 10 mg/h vs placebo. The primary endpoint of 
each study was comprised of 1) the occurrence of vasospasm-related morbidity and 
all-cause mortality within 6 weeks post-aSAH and 2) the occurrence of all-cause morbidity 
and mortality within 6 weeks post-aSAH. If it was demonstrated that clazosentan decreased 


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the occurrence of the former endpoint, the latter would also have been analyzed. 
Vasospasm-related morbidity and all-cause mortality was defined as death (all-cause), 
and/or new cerebral infarction due to vasospasm, and/or DIND due to vasospasm. 
All-cause morbidity and mortality was defined as any of these events, irrespective of 
underlying cause. In both studies, the primary analysis, performed using a 
Cochran-Mantel-Haenszel (CMH) test adjusting for pre-procedure World Federation of 
Neurological Societies (WFNS) grade, showed a statistically significant difference 
between the two treatment groups in the occurrence of vasospasm-related morbidity and 
all-cause mortality. In AC-054-305, this endpoint was reached in 28.8% of the subjects in 
the placebo arm and in 13.6% of the subjects in the clazosentan arm (p = 0.0055), 
corresponding to a relative risk reduction of 53% in the clazosentan-treated subjects. There 
was no statistically significant difference between treatment groups in the occurrence of 
all-cause morbidity and mortality. This endpoint was reached in 41.4% of the subjects in 
the placebo arm and in 33.0% of the subjects in the clazosentan arm (relative risk reduction 
= 20%, p = 0.1871). In AC-054-306, this endpoint was reached in 39.6% of the subjects in 
the placebo arm and in 16.2% of the subjects in the clazosentan arm (p = 0.0001), 
corresponding to a relative risk reduction of 59% in the clazosentan-treated subjects. There 
was no statistically significant difference between treatment groups in the occurrence of 
all-cause morbidity and mortality. This endpoint was reached in 57.5% of the subjects in 
the placebo arm and in 45.7% of the subjects in the clazosentan arm (relative risk reduction 
= 21%, p = 0.0880). 
The safety of clazosentan is addressed in Section 1.6. 
More detailed information can be found in the IB [Clazosentan IB]. 
1.4.4 Clazosentan dose rationale 
In the CONSCIOUS-1 study (Phase 2), the dose of 15 mg/h showed a larger effect in the 
prevention of moderate to severe cerebral vasospasm than lower doses (relative risk 
reduction 0.65; 95% CL 0.47–0.78) as compared to placebo. In the Phase 3 studies, 
clazosentan could reduce the use of rescue therapy, including ETx, and at the 15 mg/h dose 
also showed an effect on reducing DINDs and the overall combined morbidity and 
mortality endpoint [see Section 1.4.3].  
The efficacy of doses lower than 15 mg/h was inconsistent in clinical studies. A dose of 
5 mg/h did not show a statistically significant effect on the combined vasospasm-related 
morbidity/mortality endpoint in the CONSCIOUS-2 and CONSCIOUS-3 studies. In 
CONSCIOUS-1, a smaller effect on the prevention of angiographic cerebral vasospasm 
was observed at clazosentan doses of 1 mg/h and 5 mg/h. 


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The 15 mg/h dose has therefore been chosen for further development. Based on nonclinical 
and limited clinical data, clazosentan has shown an ability to reverse established cerebral 
vasospasm at doses similar to those effective in the prevention of vasospasm. 
Over 1800 subjects with aSAH have been treated with clazosentan, of whom 314 received 
the 15 mg/h dose. The safety profile of clazosentan is well known and its potential adverse 
effects are manageable in an intensive care unit (ICU) setting. 
1.5 Rationale of the study 
Clazosentan, an anti-vasospastic drug, is expected to provide optimal benefit when initiated 
early in the pathophysiological sequence aSAH → vasospasm → vasospasm-related 
ischemic complications.  
Nimodipine, a calcium channel blocker, is the only therapy that was widely granted 
approval for the prevention of ischemic complications of aSAH 30 years ago. Despite 
improvement in ICU management, clinical deterioration due to DCI remains a serious 
concern and represents an unmet medical need today. These episodes of deterioration must 
be avoided because if left untreated they may lead to brain infarcts, aggravate or degrade 
into further ICU complications (e.g., coma with pulmonary complications), increase the 
length of stay in ICU, and trigger the performance or administration of invasive ETx 
(angioplasty or multiple sessions of intra-arterial vasodilators). ETx is a labor intensive and 
highly specialized procedure, and not all neurosurgical departments have the expertise, 
facilities and necessary resources to perform it. Particularly in centers/countries which do 
not have the ability to perform ETx, there is a high unmet medical need for a proven 
alternative therapy, which could be readily available. The availability of an effective, 
standardized, minimally invasive treatment of cerebral vasospasm, that reduces the risk of 
experiencing DCI and the subsequent need for invasive, resource intensive and risky ETx, 
would therefore constitute a clinically meaningful benefit to patients. 
Based on the totality of the data from post-hoc analyses of the CONSCIOUS-2 and 
CONSCIOUS-3 studies, and data from the REVERSE study, a population at high risk for 
vasospasm-related ischemic complications has been identified [see Section 4.1]. This 
enriched population is likely to present more vasospasm-related morbidity than the general 
aSAH population investigated thus far. The enrichment strategy restricts the use of 
clazosentan to those subjects who are most likely to benefit from it, thus maximizing the 
overall benefit-risk profile. 
1.6 Summary of known and potential risks and benefits 
Clazosentan is expected to prevent the unfavorable consequences of vasospasm, such as 
neurological deterioration due to DCI, cerebral infarction, and ultimately poor clinical 
outcome. By preventing vasospasm-related neurological deterioration, it is expected that 
the administration of clazosentan will also decrease the use of endovascular rescue therapy. 


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Data from the previous CONSCIOUS studies demonstrate the potential of clazosentan to 
provide a clinical benefit on these various components of the disease process 
[see Sections 1.4.3 and 4.2]. Data from these studies, demonstrating the effect of 
clazosentan on top of standard of care including oral nimodipine, are the basis for the 
REACT study assumptions; primary endpoint event rates of 28% and 14% are expected in 
the placebo and clazosentan arms, respectively, representing a 50% relative reduction in 
the incidence of events in subjects treated with clazosentan. Hence, the totality of the data 
collected on the use of clazosentan in subjects with aSAH suggests that there is a high 
probability for an additional benefit when clazosentan is used as an add-on therapy to 
nimodipine in the treatment of this emergency indication. 
The safety profile of clazosentan across the previously conducted studies showed an 
increased incidence of hypotension, lung complications (primarily due to pleural effusion, 
pulmonary edema, and pneumonia), anemia, and abnormal liver tests in the clazosentan 
groups compared with placebo. There was no clear dose relationship for the incidence of 
most adverse events (AEs), across doses used in the three CONSCIOUS studies. The safety 
profile of clazosentan was confirmed in the two Japanese Phase 3 studies.  
The majority of the lung complication events were related to fluid retention, which is a 
known effect of ERAs [Stuart 2013]. The safety of clazosentan administered concomitantly 
with nimodipine has been studied in the clinical program in an aSAH population. The 
population pharmacokinetic/pharmacodynamic analysis performed in the CONSCIOUS-2 
study showed no significant effect of clazosentan on concomitant nimodipine 
pharmacokinetics. AEs from the CONSCIOUS-2 study showed that lung complications 
were more frequently reported in the combined clazosentan + nimodipine group (41.1%) 
compared to the group clazosentan without nimodipine (29.1%). The most frequently 
reported lung complication was pulmonary edema which was reported more frequently in 
the combined clazosentan + nimodipine group (10%) compared to clazosentan without 
nimodipine (3.6%). These results suggest that nimodipine may increase the frequency of 
lung complications, mainly pulmonary edema, when given concomitantly with 
clazosentan, due to the known pharmacological effects of both drugs. 
In addition, because of the vasodilatory properties of nimodipine, ventilation perfusion 
mismatch phenomenon may be potentiated when nimodipine is administered together with 
clazosentan. The Patient Management Guidelines [Appendix 3] provide recommendations 
on temporary/permanent discontinuation of nimodipine and/or clazosentan.  
Hypotension and decrease in BP variables occurred as a result of a systemic vasodilatory 
effect common to ERAs. Few subjects treated with clazosentan discontinued treatment due 
to hypotension.  


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As observed with other ERAs, treatment with clazosentan was associated with a decrease 
in hemoglobin concentration. This effect is attributed to plasma volume expansion, related 
to fluid retention as there was no evidence to indicate hemolysis, bleeding, or bone marrow 
depression.  
Clazosentan administration was also associated in some of the studies with a trend for 
increase in supraventricular arrhythmias.  
The following measures are implemented in the protocol to minimize the risks for the 
subjects participating in the study: 
• Exclusion of subjects with unresolved pulmonary edema or significant pneumonia or 
hypoxia (PaO2/FiO2 < 200) [see exclusion criterion 16 in Section 4.4]; 
• Exclusion of subjects with refractory hypotension [see exclusion criterion 15 in 
Section 4.4]; 
• Exclusion of subjects with significantly abnormal serum bilirubin and/or known or 
suspected liver cirrhosis or moderate to severe liver impairment [see exclusion criterion 
13 in Section 4.4]; 
• Requirement to receive study drug in an ICU (or equivalent) environment and strict 
recommendations regarding fluid management and BP control in the Patient 
Management Guidelines [see Appendix 3]; 
• Frequent monitoring of vital signs including BP during the treatment period;  
• Regular sampling for protocol-mandated hematology (including hemoglobin) and 
clinical 
chemistry 
(including 
aspartate 
aminotransferase 
[AST], 
alanine 
aminotransferase [ALT], bilirubin) assessments during the treatment period; 
• Study-specific criteria for interrupting or permanently discontinuing study treatment 
[see Sections 5.1.3.3.6 and 5.1.3.4.1]; 
• In addition, safety and efficacy data will be monitored by an Independent Data 
Monitoring Committee (IDMC) [see Section 3.3.1]; 
Information concerning the potential effect of clazosentan on spermatogenesis, and 
potential risks associated with pregnancy and lactation are described in the IB 
[Clazosentan IB].  
2 
STUDY OBJECTIVES 
The overall objective of this study is to determine the clinical efficacy of clazosentan in a 
population at high risk for developing ischemic complications post-aSAH and to further 
evaluate its safety and tolerability in this population. 


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2.1 Primary objective 
To determine the efficacy of clazosentan in preventing clinical deterioration due to DCI, 
in subjects with aSAH. 
Efficacy will primarily be assessed based on a reduction in the occurrence of clinical 
deterioration due to DCI up to 14 days post-study drug initiation. 
2.2 Secondary objectives 
• To evaluate the effect of clazosentan on the occurrence of clinically relevant cerebral 
infarction at Day 16 post-study drug initiation defined as: 
  
− all-cause cerebral infarction ≥ 5 cm3 or  
− cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI 
• To evaluate the effect of clazosentan on long-term clinical outcome, cognition, and 
health-related Quality of Life (QoL) at Week 12 post-aSAH and QoL at Week 24 
post-aSAH. 
• To evaluate the safety and tolerability of clazosentan in the selected population up to 
24 hours post-study drug discontinuation. 
2.3 Other objectives 
• To evaluate the effect of clazosentan on healthcare resource utilization. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, 
parallel-design, Phase 3 study. 
Subjects will be randomized 1:1 to clazosentan 15 mg/h or placebo, stratified by their 
WFNS grade at hospital admission (1–2 vs 3–5), patient population (high-risk prevention 
vs early treatment*), and age at hospital admission (≤ 60 and > 60 years).  
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
Overall the study will enroll 400 subjects in 2 treatment arms; 200 subjects per arm. 
The study will be conducted at approximately 100 sites in approximately 15 countries. 
Once randomized, the subject will enter a double-blind treatment period of a maximum 
duration of 14 days, followed by a safety follow-up period of 24 hours and an extended 
follow-up period for safety and efficacy assessment that terminates with an End-of-Study 
(EOS) visit at Week 24 post-aSAH see Section 3.1.1.  


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3.1.1 Study periods 
An overview of the study periods and “visits” is provided below. Details of each period are 
described in Section 7.1. 
The study comprises the following consecutive periods: 
Screening period: Starts with the signature of the informed consent form (ICF) and ends 
with subject randomization. During the screening period, the subject will be evaluated for 
eligibility for the study based on the inclusion and exclusion criteria. 
Informed consent will be obtained from the subject or proxy, and/or a third party, according 
to local regulations, and signed by the investigator or delegate, prior to performing any 
assessment that is considered to be specifically mandated by the study.  
The duration of the screening period is short, since subjects must be randomized in a 
timeframe that allows study drug to be initiated within 96 hours following the time of the 
aneurysm rupture [see inclusion criterion number 5 in Section 4.3].  
Treatment period: Starts immediately with the baseline assessments followed by the 
initiation of study drug infusion and ends with the permanent discontinuation of study drug.  
Treatment duration is dependent on the subject’s individual clinical course and the 
investigator’s judgment on the perceived need to continue the study drug [see 
Section 5.1.3.3.4 for further details].  
For subjects in the high-risk prevention group, treatment will start within 96 hours 
following the time of the aneurysm rupture and be administered where possible for 14 days. 
For subjects that require early discharge from the ICU (or equivalent environment), study 
drug must be administered for a minimum of 10 days. This duration of administration 
covers the period when vasospasm is most likely to occur. 
For subjects in the early treatment group*, treatment must begin within 24 hours of the 
time of the angiogram documenting the cerebral vasospasm necessary for entry into the 
study. Treatment will be administered for a minimum of 6 days and a maximum of 14 days.  
The treatment period includes the baseline assessments performed just prior to study drug 
start and all assessments during study drug administration. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
Observation period for the primary endpoint: This period covers the interval over 
which the subject may qualify for the primary endpoint of the study. It starts with the 
initiation of study drug infusion and ends on and includes Day 14 post-study drug initiation 


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irrespective of treatment duration. Subjects must not be discharged from the hospital earlier 
than Day 14 (and not prior to performing the 24-hour safety follow-up period). 
24-hour safety follow-up period: Starts with the permanent discontinuation of study drug 
and ends 24 hours later [see Section 7.1.3].  
The End-of-Treatment (EOT) assessments are included in this period. These assessments 
are performed within 2 hours following permanent discontinuation of study drug.  
Subjects must not be discharged from the hospital until the end of this period. 
Extended follow-up period: Starts after the 24-hour safety follow-up period and ends with 
the EOS visit, occurring 24 weeks after the aSAH [see Section 7.1.4].  
EOS (individual subject): This is defined as the last visit performed for the study (i.e., the 
EOS visit, performed 24 weeks after the aSAH), or the date of premature discontinuation 
from the study, if applicable [see Section 7.1.8]. 
EOS (study level): This time point occurs when the last subject completes his/her EOS 
visit. 
The overall study design is depicted in Figure 1. 


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Figure 1 
Study design 
Note: The study design of the early treatment group is provided below although recruitment into this group was 
discontinued from protocol version 6 onwards. 
 
 


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3.1.2 Study duration 
The study starts with the first subject, first visit and ends with the last subject, last visit. 
The study is expected to last approximately 47 months. 
The duration of participation in the study for an individual subject is expected to be 
approximately 6 months (from informed consent to the EOS visit). 
3.2 Overall study design rationale 
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group study designed to assess the efficacy and safety of clazosentan in preventing 
clinical deterioration due to DCI, in subjects with aSAH treated by endovascular coiling or 
surgical clipping, and receiving HD therapy with vasopressors and fluids. Study drug will 
be administered on top of standard aSAH treatment including oral or intravenous (i.v.) 
nimodipine when this is indicated according to the investigator. 
The use of a placebo is justified in the current study design, because all subjects will be 
permitted to receive nimodipine post-aSAH. Clazosentan will therefore be tested vs 
placebo on top of existing approved standard therapy, and subjects will be treated 
according to local medical practice if complications occur. 
Subjects will be stratified by potential confounders for clinical outcome such as their 
hospital admission WFNS grade (1–2 vs 3–5), patient population (high-risk prevention vs 
early treatment*), as well as their admission age (≤ 60 and > 60 years). 
In aSAH, WFNS grade at admission and age are strong predictors of later outcomes 
[Rabinstein 2004, Macdonald 2017]. Elderly subjects as well as those with poor grade at 
admission tend to have a less favorable long-term outcome. In addition, data from the 
CONSCIOUS-2 study of clazosentan indicated a stronger effect of clazosentan on reducing 
morbidity/mortality events in subjects with a WFNS grade of 3 to 5 at admission than those 
subjects with WFNS grades 1 and 2 [Macdonald 2011].  
Stratification by patient population (high-risk prevention group vs early treatment group*) 
is based on the fact that these two populations have never been investigated in the same 
study and may have slightly different outcomes. 
The primary endpoint will be assessed during an observation period of 14 days after the 
day of the start of infusion. This covers the period during which DCI is most likely to occur 
and the maximum treatment duration for an individual subject. 
The follow-up period continues from the end of study drug administration until EOS. At 
Week 12 post-aSAH, a time point that is clinically meaningful, long-term clinical outcome, 
QoL, and cognition are to be assessed. QoL will be re-assessed and employment status will 
be collected at Week 24.  


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*Recruitment into the early treatment group was discontinued from protocol version 6 onwards following a 
recommendation from the IDMC. 
3.3 Study committees 
3.3.1 Independent Data Monitoring Committee 
An IDMC will have overall responsibility for safeguarding the interests of subjects by 
monitoring unblinded safety and efficacy data obtained in the study at regular intervals, 
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 is 
empowered to recommend modifications to the protocol or to prematurely discontinue the 
study in order to enhance/preserve subject safety. The composition and operation of the 
IDMC is described in an IDMC charter. 
An independent statistical analysis center (ISAC), not otherwise involved with study 
conduct, will perform the analyses and generate unblinded analysis reports exclusively for 
review by the IDMC. 
3.3.2 Independent Radiology Committee 
The Independent Radiology Committee (IRC) is composed of radiologists who are 
independent from the study/sponsor and blinded to treatment allocation.  
The radiologists will retrospectively review the angiograms and CT scans submitted for 
each randomized subject to confirm: 
• the presence of common findings and clot size on the hospital admission CT scan, 
• the absence of exclusionary CT findings on the pre-randomization CT scan, 
• the presence and severity of cerebral vasospasm on the baseline angiograms 
(pre-randomization, for subjects randomized into the early treatment group*) and 
post-baseline angiograms (all subjects, after study drug initiation), 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
• the presence, location, and volume of new and worsened cerebral infarcts at Day 16 
post-study drug initiation. 
The composition and operation of the IRC is described in an IRC charter. 
3.3.3 Clinical Event Committee 
The Clinical Event Committee (CEC) is composed of clinicians with expertise in aSAH, 
who are independent from the study/sponsor, and who are blinded to treatment allocation. 
The committee will determine, based on a charter, whether the primary endpoint and the 
first component of the main secondary endpoint (infarcts ≥ 5 cm3) have been met. 
The clinicians will review clinical and imaging data from all subjects on an ongoing basis 
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endpoint. They will also adjudicate cases for the presence of a new or worsened cerebral 
infarct ≥ 5 cm3, based on the central review of CT scans performed by the IRC 
[Section 3.3.2] or other available data when the Day 16 CT scan is missing.  
The composition, operation, and adjudication rules of the CEC is described in a CEC 
charter. 
4 
STUDY POPULATION 
4.1 Selection of study population 
The REACT study will enroll a population of subjects at high risk of developing DCI, 
including those with either a high risk of developing cerebral vasospasm, and those in 
whom vasospasm has already developed but is not yet associated with significant 
neurological deterioration*. 
Although these subjects may present initially with different clinical features, their common 
factor is the high probability they have for developing DCI. If left untreated, the majority 
of those at high risk of developing vasospasm will indeed go on to develop vasospasm, and 
a proportion of subjects with asymptomatic vasospasm will transition to a state of 
vasospasm associated with neurological deterioration. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
4.2 Rationale for the selection of the study population 
1) Subjects at high risk of vasospasm (high-risk prevention): 
The subjects at the early stage of the disease continuum described above are those who are 
at high risk of developing cerebral vasospasm. These subjects are characterized by the 
presence of a large quantity of subarachnoid blood on their hospital admission CT scan, 
defined as follows: 
A “thick and diffuse clot” is defined as a thick confluent clot, more than 4 mm in thickness, 
involving 3 or more basal cisterns. 
The amount of blood on the initial CT scan is known to correlate with the development of 
symptomatic cerebral vasospasm, cerebral infarction, and poor clinical outcome 
[Frontera 2009]. A recent review concluded that the amount of blood observed on the 
admission CT scan was the only consistent risk factor for cerebral vasospasm and delayed 
ischemic complications after aSAH [Inagawa 2016]. 
Pre-planned subgroup analyses were performed on the “thick and diffuse clot” high-risk 
population in the CONSCIOUS-2, and -3 studies. In these studies, it was observed in the 
placebo groups that subjects with “thick and diffuse clots”, who represented approximately 
60% of the overall subject population, developed 2–3 times more clinical deterioration due 
to DCI (known as DINDs in these studies), and up to 4 times more cerebral infarction 
compared to subjects with less blood on their initial CT scan. In CONSCIOUS-2, 29% of 


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placebo-treated subjects with a “thick and diffuse clot” experienced an episode of DIND 
vs 9% in the “other clot size” group. In CONSCIOUS-3, the incidences of DIND in the 
same populations were 27% and 11%, respectively. In CONSCIOUS-2, new cerebral 
infarction due to vasospasm was observed in 22% of the placebo-treated subjects with a 
“thick and diffuse clot” compared to 6% in the “other clot size” group. In CONSCIOUS-3, 
the respective incidences of new cerebral infarction were 16% and 10%. In the 
CONSCIOUS-2 and -3 studies, it was observed that the subjects with “thick and diffuse 
clots” experienced poor long-term clinical outcome twice as often as the other subjects. 
In this subgroup of subjects with severe aSAH in CONSCIOUS-3, a clinically and 
statistically significant relative risk (RR) reduction of 56% on the “clinical deterioration 
due to DCI” endpoint (known as DIND in this study) was obtained with the 15 mg/h dose 
of clazosentan vs placebo. In parallel with this reduction in clinical deterioration, the 
clazosentan-treated subjects received 65% less rescue therapy for vasospasm than the 
placebo groups and showed a trend for a reduction in new cerebral infarcts due to 
vasospasm. 
The clinical meaningfulness and known correlation between DCI, cerebral infarction, and 
poor long-term outcome has been extensively described in the literature [Rosengart 2007, 
Frontera 2009, Rabinstein 2003]. Data from the CONSCIOUS studies also show a 
correlation between DIND / new cerebral infarction and poor clinical outcome. The 
high-risk population is therefore expected to benefit clinically from a prevention strategy. 
Conversely, in the aSAH population with lower blood load on admission CT scan, 
subsequent vasospasm was observed less frequently, and the expected smaller benefit of 
clazosentan may not be sufficient to justify the potential risk associated with clazosentan 
treatment without demonstration of established vasospasm. Therefore, subjects with less 
subarachnoid blood on their hospital admission CT scan are excluded from clazosentan 
treatment unless they develop subsequent vasospasm (see below). 
Subjects with large (> 50 mL) intra-cerebral hematoma as well as extensive 
intra-ventricular hemorrhage (IVH) will also be excluded [see exclusion criteria 5 and 6 in 
Section 4.4] as these conditions are known to be independent factors for poor prognosis 
[Meneghelli 2016]. 
2) Subjects with confirmed vasospasm (early treatment)*: 
Some subjects more advanced in their disease process may have confirmed cerebral 
vasospasm, detected on a routinely performed angiogram, prior to the development of 
significant neurological deterioration. In the REACT study, these asymptomatic or 
minimally symptomatic subjects who do not have “thick and diffuse clot” on the hospital 
admission CT scan, will not be excluded from study participation as they can still 
potentially benefit from treatment with clazosentan. It is expected that their risk for 
developing clinical deterioration due to DCI, cerebral infarction, and poor clinical outcome 
will be as high as that observed in the high-risk prevention subjects. In order to prevent 
ischemic complications, treatment must be initiated early enough after the confirmation of 


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vasospasm. Subjects who have already significantly deteriorated will therefore be excluded 
from the study. 
Data from the pilot study REVERSE indicate that clazosentan was associated with a limited 
effect on large proximal vasospastic vessels 3 hours after the infusion start, but showed a 
relevant effect on the distal cerebral circulation. This vasospasm-reversing effect may be 
particularly relevant for patients who are not candidates for intra-arterial intervention, 
when intra-arterial intervention is not available, or to minimize the use of this invasive 
intervention. The overall effect of clazosentan on established cerebral vasospasm may be 
sufficient to prevent vasospasm-related complications such as clinical deterioration due to 
DCI and cerebral infarction, and therefore explains the inclusion of subjects with early 
confirmed vasospasm into the REACT study.  
In summary, the target population for Phase 3, namely the high-risk vasospasm prevention 
and early vasospasm treatment population as described above, will be easily identified by 
physicians using routine imaging assessments post-aSAH, and these subjects will be 
treated as soon as possible with the objective of preventing clinical deterioration after 
aSAH. This strategy restricts the use of clazosentan to those subjects who are most likely 
to benefit from the drug, thus maximizing the overall benefit-risk profile. Furthermore, 
such an enrichment strategy will allow higher event rates to be achieved and consequently 
a reasonable sample size in this orphan indication. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards following a 
recommendation from the IDMC. 
4.3 Inclusion criteria 
For inclusion in the study, the subject must fulfill all of the following inclusion criteria. It 
is not permitted to waive any of the criteria for any subject. 
1. Written informed consent* to participate in the study must be obtained from the subject 
or proxy / legal representative at any time from hospital admission to prior to initiation 
of any study-mandated procedure. 
*Consent will be obtained by a procedure that is based on local regulations and acceptable to local 
authorities (including, e.g., deferral of consent). The consent form must also be signed by the investigator 
or delegate prior to any study-mandated procedure. Further details may be found in Section 12.3. 
Information that is available prior to the consent as part of local standard practice can be used to determine 
subject eligibility for the study, as applicable. 
2. Males and females aged 18 to 70 years (inclusive, at hospital admission). 
3. Subjects with a ruptured saccular aneurysm, angiographically confirmed by DSA or 
CTA, which has been successfully secured* within 72 hours of rupture, by surgical 
clipping or endovascular coiling.** 


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*A successfully secured aneurysm (clipping or coiling) is defined as > 80% exclusion by volume with 
< 50% narrowing of parent vessel or adjacent branches (assessed locally). In addition, successful implies 
no additional intervention planned on the repaired aneurysm in the 3-month period following the initial 
procedure. 
**The aneurysm may have been secured by both clipping and coiling. Stent-assisted coiling and other 
endovascular devices (e.g., 
® device) are not allowed. The temporary use of approved devices during 
the coiling procedure is allowed, provided their use does not require anti-platelet or other agents affecting 
clotting mechanisms. Determination of date/time of aneurysm rupture is described in Section 7.2.1.1. 
4. WFNS grades 1–4 (based on Glasgow Coma Scale [GCS]) assessed after recovery from 
the aneurysm-securing procedure and after external ventricular drainage for 
hydrocephalus, if required. 
5. High-risk prevention: Subjects with a “thick and diffuse clot”* on the hospital 
admission CT scan, absence of cerebral vasospasm at the time of randomization, and 
the possibility to start study drug in the ICU (or equivalent environment where all 
protocol assessments can be performed and the Patient Management Guidelines 
followed), within 96 hours following the time of the aneurysm rupture. 
*Thick and diffuse is defined as a thick confluent clot, more than 4 mm in thickness, involving 3 or more 
basal cisterns [see Appendix 1 for further details]. 
6. A) Presence of a cerebral CT scan performed at least 8 hours post aneurysm-securing 
procedure and within 24 hours prior to randomization.  
6. B) Absence of a significant (e.g., symptomatic or large) new or worsened* cerebral 
infarct or re-bleeding of the repaired aneurysm on the post-procedure CT scan. 
*This CT scan will be compared with the admission and any routinely performed post-procedure CT 
scan(s) to detect new or worsened infarcts and re-bleeding which appear after the aneurysm-securing 
procedure.  
7. A woman of childbearing potential [see definition in Section 4.5] is eligible only if the 
serum pregnancy test performed during the screening period is negative.  
Agreement must be obtained to take the necessary precautions to avoid pregnancy from 
hospital discharge until 30 days post-study drug discontinuation [see Section 4.7]. 
If breastfeeding, agreement must be obtained to refrain for the duration of the treatment 
with study drug and until 30 days post-study drug discontinuation.  
8. Males are eligible for study participation only if they agree to take the necessary 
precautions to avoid pregnancy in a female partner from hospital discharge until 
30 days post-study drug discontinuation [see Section 4.8]. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject. 


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aSAH, aneurysm-securing procedure, vasospasm 
1. Subjects with SAH due to causes other than a saccular aneurysm (e.g., trauma or 
rupture of fusiform or mycotic aneurysms, SAH associated with arterio-venous 
malformation, vertebral dissections). 
2. Subjects with at least one unruptured aneurysm for whom a subsequent intervention is 
planned within 3 months of the aSAH.  
3. Significant bleeding post aneurysm-securing procedure (e.g., due to intra-ventricular 
drain, intra-cerebral hemorrhage, epidural hematoma, vessel dissection or rupture, 
re-bleeding of the repaired aneurysm*), based on investigator judgment.  
*Re-bleeding prior to the aneurysm-securing procedure is not an exclusion criterion. 
4. Intra- or peri-aneurysm securing procedure complication, requiring non-routine 
medical or interventional treatment such as administration of an antithrombotic or 
anti-platelet agent (e.g., abciximab), which is not completely resolved prior to 
randomization.  
5. IVH on the hospital admission CT scan, filling more than 50% of both lateral ventricles 
and with involvement of the 3rd and 4th ventricles. 
6. Intra-cerebral hemorrhage on the hospital admission CT scan, with an approximate 
volume of > 50 mL. 
7. Presence of cerebral vasospasm at hospital admission (initial admission or transfer from 
another hospital) believed to be associated with a prior bleed (i.e., occurring before the 
bleed for which the subject is currently hospitalized). Vasospasm occurring during the 
aneurysm-securing procedure is not an exclusion criterion. 
Neurological and functional status  
8. Subjects with a new major neurological deficit occurring post aneurysm-securing 
procedure,* which is attributable to the procedure and does not improve to 
pre-procedure status before randomization. 
*Evaluation for a new major neurological deficit post procedure implies the reversal of sedation (or 
waiting for the subject to recover from sedation) and the performance of a neurological examination. 
9. Subjects who are still under the influence of pharmacological sedation at the time of 
randomization or who are, for whatever reason, not evaluable for baseline and regular 
daily neurological assessments. 
10. WFNS grade 5 (based on GCS) immediately prior to planned randomization, assessed 
after external ventricular drainage for hydrocephalus, if required. 
11. Subjects with a GCS score of ≤ 9 at the time of randomization and without intracranial 
pressure (ICP) monitoring. 


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12. Modified Rankin Scale (mRS) score of 3 or higher, prior to the aSAH (i.e., due to a 
chronic condition). 
Other clinical considerations 
13. Subjects with total bilirubin > 2 × the upper limit of normal, and/or a known diagnosis 
or clinical suspicion of liver cirrhosis or moderate to severe hepatic impairment. 
14. Any concomitant condition or disease (including psychiatric and neurological 
conditions, drug abuse, severe alcoholism) which, in the opinion of the investigator, 
would affect the assessment of the safety or efficacy of the study treatment. 
15. Hypotension (systolic blood pressure [SBP] ≤ 90 mmHg) at time of randomization that 
is refractory to treatment. 
16. Unresolved pulmonary edema or significant pneumonia still present at the time of 
randomization, or severe hypoxia at the time of randomization in intubated subjects, 
defined as PaO2/FiO2 ≤ 200. 
17. High sustained ICP (> 25 mmHg lasting > 20 minutes) at time of randomization, despite 
optimal treatment, in subjects with ICP monitoring. 
18. Severe cardiac failure requiring inotropic support at the time of randomization. 
Medications and therapies 
19. Lumbar and/or cisternal drainage performed specifically to prevent or treat cerebral 
vasospasm at any time from hospital admission to randomization.  
20. Prophylactic or therapeutic administration of intra-arterial vasodilators* or ozagrel, or 
performance of cerebral angioplasty** at any time from hospital admission to 
randomization. 
*Mechanically induced vasospasm occurring during the aneurysm-securing procedure may be treated 
with local administration of vasodilators (e.g., intra-arterial, topical). 
**Balloon assisted vascular remodeling during the aneurysm-coiling procedure is permitted. 
21. Subjects for whom at the time of randomization administration of urgent rescue therapy 
(i.e., cerebral angioplasty, intra-arterial/intrathecal/intra-cisternal/intra-ventricular 
administration of vasodilators or ozagrel) is anticipated. 
22. Use of intrathecal, intra-cisternal, or intra-ventricular* thrombolytics at any time from 
hospital admission to randomization. 
*Use of thrombolytics to open an occluded drain is permitted. 
23. Administration of intrathecal, intra-cisternal, and intra-ventricular vasodilators (e.g., 
nimodipine), i.v. nicardipine (except for blood pressure control), or i.v. milrinone*, 
within 4 hours prior to randomization. 
*Administration of i.v. milrinone at any time from hospital admission to randomization is exclusionary 
if used to prevent or treat cerebral vasospasm. 


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24. Administration of i.v. fasudil or i.v. ozagrel within 24 hours prior to randomization. 
25. Use of intra-aortic balloon counter-pulsation devices at any time from hospital 
admission to randomization. 
26. Use at any time from hospital admission to randomization, of any investigational drugs, 
procedures or devices, including:  
• investigational clipping material and investigational coiling material such as liquid 
embolic material, stents or flow diverting devices, and,  
• any other medication administered to prevent or treat vasospasm, reduce ischemic 
complications, or to improve clinical outcome post-aSAH, that has not been 
approved for these specific indications by local health authorities (e.g., new 
post-hospital admission prescription of “statins”, therapeutic hypothermia). 
27. Subjects receiving strong inhibitors of organic anion transporting polypeptide 
(OATP)1B1 and OATP1B3 transporter proteins (e.g., cyclosporin A, rifampicin, 
lopinavir/ritonavir), or subjects for whom it is likely at the time of randomization that 
these medications will be started during the study treatment infusion period. 
28. Known hypersensitivity to clazosentan or any excipient in the formulation. 
4.5 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least 1 of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy, or hysterectomy; 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3 definition]); 
• Premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, 
uterine agenesis. 
The reason for not being of childbearing potential will be recorded in the electronic case 
report form (eCRF) and hospital charts. 
4.6 Breastfeeding women 
Women who were breastfeeding at the time of the aSAH must refrain for the duration of 
the treatment and until 30 days after the discontinuation of study drug. It is unknown 
whether clazosentan may be excreted into breast milk. 
4.7 Contraceptive requirements for women of childbearing potential 
Women of childbearing potential [see Section 4.5] must agree to avoid pregnancy during 
the period from hospital discharge until 30 days post-study drug discontinuation. 
One of the following highly effective methods of birth control are allowed for the study: 


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1. Sexual abstinence 
2. Intrauterine device 
3. Intrauterine hormone-releasing system 
4. Hormonal contraceptives (oral, intra-vaginal, transdermal, injectable or implantable): 
combined (estrogen and progestogen containing) or progestogen-only hormonal 
contraception associated with inhibition of ovulation, only if used together with one of 
the following barrier methods: male or female condom, cervical cap with a spermicide, 
or diaphragm with a spermicide.  
5. Bilateral tubal occlusion/ligation if performed more than 6 weeks prior to hospital 
discharge 
6. Vasectomized partner (medically assessed as successful procedure) 
The following methods are NOT considered highly effective methods of contraception for 
the study and should not be used alone: 
• Male or female condom with or without spermicide 
• Cap, diaphragm, or sponge with spermicide 
• Hormonal contraceptives (oral, intra-vaginal, transdermal, injectable or implantable): 
combined (estrogen and progestogen containing) or progestogen-only hormonal 
contraception associated with inhibition of ovulation.  
The following methods are not allowed as methods of contraception for the study: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action  
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicides only 
• Lactational amenorrhea method 
• Combination of female condom and male condom 
To ensure compliance, the study personnel must remind the subjects of the contraception 
requirements at hospital discharge and document the reminder in the medical chart. 
4.8 Contraceptive requirements for men 
Male subjects who are physiologically capable of conceiving a child (based on known 
information available to the investigator) must agree to take the necessary precautions to 
avoid pregnancy in a female partner of childbearing potential during the period from 
hospital discharge until 30 days post-study drug discontinuation.  


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Sexual abstinence or the use of a condom are considered acceptable methods of birth 
control for this purpose. 
To ensure compliance, the study personnel must remind the subjects of the contraception 
requirements at hospital discharge and document the reminder in the medical chart. 
5 
TREATMENTS 
5.1 Study treatment 
5.1.1 Investigational treatment and matching placebo 
Clazosentan is supplied in clear glass vials as a concentrated solution for continuous i.v. 
administration, after dilution.  
Each vial contains 150 mg of clazosentan in a total volume of 6 mL, providing a 
concentration of 25 mg/mL (2.5% w/v, pH 8.0 ± 0.1). Each vial contains a small volume 
of overfill. 
Matching placebo is supplied in identical clear glass vials with the same formulation as 
described above (excluding clazosentan) and the same volume. 
For instructions on study drug preparation, refer to Section 5.1.3.2 and the study-specific 
Investigational Medicinal Product (IMP) Handling and Dispensing Guidelines. For a 
description of study drug packaging and labeling, refer to Section 5.1.6.1. 
5.1.2 Treatment assignment 
A total of 400 eligible subjects will be randomized in a 1:1 ratio to clazosentan 
(200 subjects) or placebo (200 subjects), stratified by their WFNS grade at hospital 
admission (1–2 vs 3–5), patient population (high-risk prevention vs early treatment*), and 
age at hospital admission (≤ 60 and > 60 years).  
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
At the time of enrollment, after having verified that the subject meets all of the inclusion 
criteria and none of the exclusion criteria, the investigator/delegate contacts the interactive 
response technology (IRT) system to randomize the subject. The IRT system assigns a 
medication kit number to the subject, matching the treatment arm assigned according to 
the randomization list. Kit numbers will be entered in the eCRF. 
The IRT system is handled by an external independent vendor who will generate the 
randomization list. 
5.1.3 Study treatment dosing, preparation and administration 
5.1.3.1 Study drug dose 
Subjects will be administered either clazosentan, as a continuous i.v. infusion at the dose 
of 15 mg/h, or placebo at the same corresponding infusion rate [see Section 5.1.3.3.2]. 


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5.1.3.2 Study drug preparation 
Study drug must be prepared by a qualified person (e.g., pharmacy personnel or study staff) 
as appropriate, based on the investigative site’s organization and local requirements.  
The concentrated study drug will be diluted in a 500 mL bag of 0.9% sodium chloride as 
per the IMP Handling and Dispensing Guidelines. 
One study drug infusion bag will be prepared for each 24-hour treatment period. Each 
prepared infusion bag will theoretically contain enough study drug for up to 30 hours of 
administration. However, this extra volume takes into consideration the volume of study 
drug that will be “lost” after flushing and priming the i.v. tubing and indwelling i.v. 
catheter, which must occur prior to starting the study drug infusion. 
In order to adjust the timing of the start of each 24-hour period to a convenient time, it is 
possible to prepare and administer the second infusion bag prior to the end of the first 
24-hour period. However, all subsequent infusion bags will be prepared and administered 
for a full 24-hour period, and each subsequent bag will be changed at approximately the 
same time each day, even if not completely empty. 
Refer to the IMP Handling and Dispensing Guidelines for further details on preparation 
and storage of prepared study drug solution. 
5.1.3.3 Study drug administration 
5.1.3.3.1 General administration instructions 
The study drug infusion must be administered in an ICU (or equivalent environment where 
all protocol assessments can be performed and the Patient Management Guidelines 
followed), as a continuous infusion in parallel to the administration of HD therapy as per 
the Patient Management Guidelines [see Appendix 3]. Study drug may only be initiated 
once the subject’s BP and fluid status are controlled according to the Patient Management 
Guidelines. 
The study drug will be administered via a dedicated lumen of a central line or a dedicated 
peripheral line, both used exclusively for the administration of study drug for the entire 
treatment period. 0.2 µm infusion filters will be used to prevent potential particulate and 
microbial contamination of the infused solution. 
Infusion pumps will be used to administer the study drug infusion and will be calibrated 
according to local institution standards and practices.  
Further details on the technical specifications of the infusion lines/sets/filters and pumps 
which may be used can be found in the IMP Handling and Dispensing Guidelines. 
5.1.3.3.2 Dose and infusion rate 
The infusion rate (mL per hour) of the final prepared solution, corresponding to a dose of 
clazosentan 15 mg/h (or placebo), will depend on the amount of overfill contained in the 


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500 mL bag, which is to be determined and documented prior to the preparation of study 
drug for the first subject randomized into the study. Since the volume of overfill may vary 
from one batch of infusion bags to another, the amount of overfill will need to be 
determined and documented each time a new batch is used. 
The infusion rates (taking into account the amount of overfill in the bags) are indicated in 
the IMP Handling and Dispensing Guidelines. 
The dose will be constant for the entire treatment period. No dosage adjustment is foreseen 
in this protocol. For situations that may require temporary or permanent study drug 
discontinuation, refer to Sections 5.1.3.3.4, 5.1.3.3.5, and 5.1.3.4. 
5.1.3.3.3 Treatment initiation 
For subjects enrolled in the high-risk prevention group, treatment will start as soon as 
possible, but no later than 96 hours post-aSAH.  
For subjects enrolled in the early treatment group*, treatment will start no later than 
24 hours after the start time of the angiogram confirming the presence of moderate to 
severe cerebral vasospasm. This angiographic diagnosis must be made up to and including 
Day 14 post-aSAH. 
Study drug may only be initiated once the subject’s BP and fluid status is controlled 
according to the Patient Management Guidelines, and the baseline assessments have been 
performed [see Table 1 and Section 7.2]. 
The i.v. lines (infusion set and indwelling i.v. catheter) must be primed/flushed with the 
prepared study drug solution prior to starting the infusion to ensure immediate delivery of 
study drug into the circulation when the infusion pump is activated. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
5.1.3.3.4 Treatment duration 
Subjects will remain in the ICU (or equivalent) for the duration of the treatment period. 
Treatment will be administered where possible for a full 14 days (14 × 24-hour periods).  
For subjects in the high-risk prevention group, treatment will be administered where 
possible, for 14 days. For subjects that require early discharge from the ICU (or equivalent), 
study drug must be administered for a minimum of 10 days. This treatment duration covers 
the period when vasospasm is most likely to occur. 
For subjects in the early treatment group*, treatment will be administered for a minimum 
of 6 days and a maximum of 14 days. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
The above described minimum and maximum treatment durations include the time 
corresponding to temporary treatment interruptions.  


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The actual duration of treatment will depend on the subject’s clinical course, and the 
investigator’s judgment on the perceived need to continue the study drug. Unless 
permanent study drug discontinuation is believed to be in the best interest of the subject, 
study drug should be continued until the maximum duration described above, despite the 
need for escalation of medical therapy for cerebral vasospasm or cerebral ischemia, or the 
perceived lack of early efficacy. 
Study drug must be temporarily interrupted prior to any rescue therapy and must be 
resumed after the completion of the therapy, unless a decision is made to permanently 
discontinue its administration at this time. Other potential reasons for temporary 
interruption of study drug are described in Sections 5.1.3.3.5 and 5.1.3.3.6. 
Irrespective of when the study drug was discontinued, all subsequent assessments required 
during the observation period until Day 14 post-study drug initiation, as described in 
Section 7.1.4, will be performed according to the protocol. 
5.1.3.3.5 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments are not permitted by the study protocol. 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. Inability to 
achieve the target BPs as described in the Patient Management Guidelines may also lead 
to temporary interruptions. Study-specific criteria for interruption of study treatment are 
described in the following section.  
Interruptions of study treatment should be kept as short as possible.  
Any interruption due to an AE is to be recorded in the eCRF.  
Interruptions for other reasons (e.g., logistical, administrative), are to be recorded in the 
eCRF only if their duration is ≥ 15 minutes.  
EOT assessments do not need to be performed for temporary interruptions of study 
treatment. However, if an interruption is initially planned to be temporary, but study 
treatment is subsequently permanently discontinued, the EOT assessments are to be 
performed after the permanent discontinuation. 
5.1.3.3.6 Study-specific criteria for temporary interruption of study treatment 
Study drug must be temporarily interrupted prior to any rescue therapy, and must be 
resumed after the completion of the therapy, unless a decision is made to permanently 
discontinue its administration at this time.  
The Patient Management Guidelines recommend temporarily interrupting study drug 
when:  
A) the target BP cannot be achieved (after the discontinuation of nimodipine, if applicable) 


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or  
B) pulmonary ventilation/perfusion ratio mismatch is suspected (or is persistent despite 
discontinuation of nimodipine, if applicable). 
5.1.3.4 Premature discontinuation of study treatment 
The decision to prematurely and permanently discontinue study treatment may be made by 
the subject (or proxy / legally acceptable representative, if applicable), the investigator, or 
sponsor personnel. The main reason (e.g., AE, lack of efficacy, study terminated by 
sponsor) must be documented in the eCRF. 
A subject (or proxy / legally acceptable representative, if applicable) has the right to 
prematurely discontinue study treatment at any time, without any justification, by 
withdrawing from study treatment only or by withdrawing from any further participation 
in the study (i.e., premature withdrawal from the study [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 he/she believes 
that continued administration would be contrary to the best interests of the subject. 
Study treatment may be discontinued in response to an AE, lack of efficacy (including 
disease progression, worsening of subject’s condition), a protocol deviation (including 
eligibility failure, non-compliance with study requirements), a diagnostic or therapeutic 
procedure, or a laboratory abnormality. Study treatment may also be prematurely 
discontinued if the target BPs as described in the Patient Management Guidelines 
[see Appendix 3] cannot be achieved.  
Study-specific criteria for premature and permanent discontinuation of study treatment are 
described in Section 5.1.3.4.1. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until their EOS visit (i.e., at Week 24 post-aSAH), 
provided that the subject’s consent for this limited participation in the study has not been 
withdrawn. 
At the time of the premature study treatment discontinuation, the EOT assessments will be 
performed. All subsequent assessments required during the observation period until Day 14 
post-study drug initiation, as described in Section 7.1.4, will be performed according to the 
protocol. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 


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Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study are described in Sections 8.2 and 8.4, respectively. 
Subjects in the high-risk prevention group, who had their study drug permanently 
discontinued prior to the 10th calendar day of study drug administration, will be 
considered as prematurely discontinuing study drug. Subjects in the early treatment 
group* who had their study drug permanently discontinued prior to the 6th calendar 
day of study drug administration, will be considered as prematurely discontinuing 
study drug. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
5.1.3.4.1 Study-specific criteria for premature discontinuation of study treatment 
In addition to the general potential reasons for premature study drug discontinuation 
described above, the study protocol requires the premature and permanent discontinuation 
of study drug in the following situations: 
A) Inability to control or maintain BP as per Patient Management Guidelines, despite 
discontinuation of nimodipine, if applicable, and temporary study drug interruption. 
B) Persistent pulmonary ventilation/perfusion ratio mismatch suspected to be related to 
study drug administration [see Appendix 3].  
C) Presence of generalized brain edema. 
D) Presence of severe pulmonary edema. 
E) Total bilirubin increases to a level ≥ 3 × the upper limit of normal range or acute liver 
impairment is suspected.  
F) Pregnancy while on study drug; a Pregnancy Form must be completed [see 
Section 9.4.1]. 
G) Another ERA, and/or another investigational product/procedure is started during the 
treatment period. 
H) A strong inhibitor of OATP1B1 and OATP1B3 transporter proteins (e.g., cyclosporin 
A, rifampicin, lopinavir/ritonavir) is started during the treatment period. 
5.1.4 Blinding 
This study will be performed in a double-blind fashion. The investigator, study personnel, 
subjects, clinical research associates (CRAs), sponsor personnel, and vendor / Contract 
Research Organization (CRO) personnel involved in the conduct of the study will remain 
blinded to the study treatment received by the subjects during the double-blind treatment 
period until study closure. 


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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.  
The IDMC and the ISAC will be unblinded to study treatment allocation. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to the IRT vendor, sponsor authorized persons 
(i.e., Pharmaceutical Development group) who are not involved in the conduct of the study, 
and the IDMC and the ISAC. 
All study drug kits will be packaged in the same way, rendering the investigational 
treatment indistinguishable from its matching placebo. 
5.1.5 Unblinding 
5.1.5.1 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. 
5.1.5.2 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) see definition in 
Section 9.1.4 occurs in a subject participating in the study, the sponsor’s Global Drug 
Safety department will request the unblinding of the treatment assignment in order to meet 
regulatory reporting requirements. 
The treatment assignment will not be communicated to site personnel, subjects, sponsor 
CTT or any vendor/CRO personnel involved in the conduct of the study. 
Unblinded SUSAR information will be reported to respective health authorities and 
Independent Ethics Committees (IECs) / Institutional Review Boards (IRBs) and the 
IDMC only. SUSARs will be notified to investigators in a blinded fashion. 
5.1.5.3 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 an 
emergency medical event, the management of which would require knowledge of the 
blinded treatment assignment. In this case, the decision to unblind resides solely with the 
investigator and the investigator can receive the unblinded treatment assignment through 


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the IRT system. Whenever possible, and provided 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 emergency unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, the sponsor personnel must be informed about 
the reason for the unblinding 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. 
If unblinding occurs, all assessments as defined in the study protocol must still be 
performed, unless the subject withdraws consent to participate in the study. 
5.1.6 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. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.6.1 Study treatment packaging and labeling 
Study treatment is supplied in kits containing 15 vials of clazosentan or placebo [see 
Section 5.1.1 for vial descriptions], enough for 5 days of treatment.  
Additional kits to cover the entire treatment period can be requested by contacting the IRT 
system (see the IRT user manual). 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.6.2 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 (store below 30 °C/86 °F, do not freeze). 
The study sites will be supplied with study drug according to each center’s needs, 
depending on the rate of subject enrollment. Each center will have an individual supply of 
study drug, which will be re-supplied automatically as soon as a predefined minimum level 
of study drug has been reached.  
Further instructions regarding the distribution and storage of study drug are provided in the 
IMP Handling and Dispensing Guidelines. 


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5.1.6.3 Study treatment dispensing 
Each kit and each vial will have a label with a tear-off part which must be removed and 
attached to the IMP Label Log as the study drug is dispensed during the treatment period. 
An accurate record of the date and amount of study drug used to prepare the daily infusions 
for each subject must be available for inspection at any time.  
All unused vials are to be stored in the subject kit for inspection by the site monitor at 
monitoring visits. Used vials should be stored separately from the subject kit. 
The study treatment dispensing/return procedures may not be altered without prior written 
approval from the sponsor (e.g., in the event that a local process requires immediate 
destruction of vials after preparation and of any unused vials once subject has finished 
treatment).  
Details on how to record the dispensing of study drug are available in the IMP Handling 
and Dispensing Guidelines. 
5.1.6.4 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 study drug 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. 
5.1.7 Study treatment accountability and compliance with study treatment 
5.1.7.1 Study treatment accountability 
The inventory of study treatment dispensed and returned (i.e., study treatment 
accountability) must be performed by the study staff daily during the treatment period. It 
is recorded on the IMP dispensing and accountability log and checked by the CRA during 
site visits and at the end of the study if needed. The log will contain information including 
the kit and vial numbers, the date/time of study drug preparation, the identity of the person 
preparing the study drug, and the storage conditions of the prepared infusion bags. The 
used and unused study medication vials must be retained at the site until they are verified 
by the CRA. Exceptions may occur e.g., in the event that a local process requests immediate 
destruction of the study treatment. Local study treatment destruction processes must be 
provided to, and approved by, the sponsor. 
5.1.7.2 Study treatment compliance 
Study treatment compliance is a measure of how closely the protocol instructions for 
administering study drug were adhered to.  


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The start and end date/time of study drug administration and the hourly dose is recorded in 
the eCRF. As dose adjustments of study drug are not permitted by the study protocol, only 
the dose of 15 mg/h is expected.  
Interruptions of study treatment are allowed by the protocol but should be kept as short as 
possible. Any interruption due to an AE is to be recorded in the eCRF. Interruptions for 
other reasons (e.g., logistical, administrative), are to be recorded in the eCRF only if their 
duration is ≥ 15 minutes.  
Over the entire treatment period, compliance is expected to be 100%. Any non-compliance 
(administration of study drug at a rate other than 15 mg/h), will be considered as a protocol 
deviation. The investigator must document in the subject’s source notes the reasons for this 
non-compliance and any actions to be taken to avoid future recurrences. 
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
For the purposes of this study, a previous therapy is defined as any treatment for which the 
end date is prior to the signature of the ICF. 
A study-concomitant therapy is defined as any treatment that is ongoing or initiated after 
the signature of the ICF, or initiated up to 24 hours post-study drug discontinuation. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at the 
start of study treatment or is initiated during the treatment period until the time of 
permanent study drug discontinuation. 
5.2.2 Concomitant therapy required to control blood pressure and fluid status 
(mandatory compliance with the Patient Management Guidelines) 
Due to the potential for hypotension with clazosentan administration, prior to initiating 
study drug, BP and fluid status will be controlled, if needed, with i.v. vasopressors and 
fluid administration as per the study-specific Patient Management Guidelines 
[see Appendix 3]. Vasopressor and fluid therapy will be administered as required, 
according to these guidelines, until the permanent discontinuation of study drug. 
5.2.3 Allowed concomitant therapy 
5.2.3.1 Local standard of care 
The usual standard of care for the management of aSAH is allowed until the primary 
endpoint assessment at 14 days post-study drug initiation, except for those therapies listed 
in the “forbidden concomitant medication” section, and must be documented in the medical 
charts.  
Nimodipine (oral or i.v.) may be administered for the usual duration if it is routine standard 
of care at the site. 


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“Statins” (e.g., simvastatin, pravastatin) may only be administered if the subject was 
receiving them chronically for treatment of high cholesterol. 
Vaccines (including those for COVID-19) may be administered at any time during the 
study. They will be recorded as described in Section 5.2.5.   
5.2.3.2 Rescue therapy 
For the purpose of this study, rescue therapy refers to the escalation of medical therapy 
beyond standard HD therapy, for the treatment of refractory vasospasm. Refractory 
vasospasm is characterized by a minimum of 2-points worsening on either of the 
neurological scales and no response to HD therapy. The following therapies are considered 
rescue therapies:  
• balloon angioplasty, 
• intra-arterial/intrathecal/intra-cisternal/intra-ventricular administration of vasodilators 
or ozagrel. 
The decision to administer the above rescue therapies is based on local standard of care 
and is allowed at any time during the study for refractory vasospasm. The refractory nature 
is to be documented in the eCRF.  
Intravenous administration of vasodilators (e.g., nicardipine, milrinone) are allowed as 
rescue therapy only if preceded by intra-arterial administration of a vasodilator.  
The other medications in the “forbidden concomitant therapy” section below (with their 
respective routes of administration) are not considered as rescue therapies and their 
administration is forbidden until Day 14 post-study drug initiation. 
Study drug must be temporarily interrupted prior to any rescue therapy, and must be 
resumed after the completion of the therapy. 
5.2.4 Forbidden concomitant therapy 
The following medications/therapies are forbidden until the primary endpoint assessment 
at Day 14 post-study drug initiation, due to their potential to interfere with the evaluation 
of efficacy or safety, or due to the potential for a drug-drug interaction with study drug 
(refer to the IB for more information [Clazosentan IB]). Those that are described above 
under “rescue therapy” are permitted in the treatment of refractory vasospasm, but are 
forbidden otherwise. 
• Intra-aortic balloon device. 
• Lumbar and/or cisternal drainage for the prevention of cerebral vasospasm / DCI. 
• Milrinone i.v., nicardipine i.v.*, and intrathecal/intra-cisternal/intra-ventricular 
vasodilators (e.g., nimodipine), must be discontinued at least 4 hours prior to 
enrollment.  


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*Administration of i.v. milrinone at any time from hospital admission to randomization 
is exclusionary if used to prevent or treat cerebral vasospasm. Nicardipine i.v. may be 
used at any time for blood pressure control. 
• Magnesium i.v., albumin i.v., or plasma volume expander if administered specifically 
for the prevention of cerebral vasospasm and/or DCI. 
• Thrombolytics 
(including 
intrathecal, 
intra-cisternal, 
and 
intra-ventricular, 
administration) and antifibrinolytics (e.g., tranexamic acid). Use of thrombolytics to 
open an occluded drain is permitted. 
• Hypertonic saline i.v., if administered in the absence of hyponatremia, brain edema, or 
high ICP. 
• Mannitol i.v., if administered in the absence of brain edema or high ICP. 
• Strong inhibitors of OATP1B1 and OATP1B3 transporter proteins (e.g., cyclosporin 
A, rifampicin, lopinavir/ritonavir). 
• Other ERAs. 
• Any investigational drugs, procedures, or devices, including any other medication 
administered to prevent/treat cerebral vasospasm that has not been approved for this 
specific indication by local health authorities (e.g., therapeutic hypothermia, “statins”). 
• Traditional medicines (i.e., plant-, animal-, or mineral-based medicine, such as 
traditional Chinese medicine). 
Study treatment must be permanently discontinued if one of the following is initiated 
during the treatment period: 
• Another ERA. 
• Another investigational product/procedure. 
• A strong inhibitor of OATP1B1 and OATP1B3 transporter proteins (e.g., cyclosporin 
A, rifampicin, lopinavir/ritonavir). 
5.2.5 Reporting of previous/concomitant therapy in the eCRF 
All previous and study-concomitant therapies taken/administered less than or equal to 
24 hours prior to randomization into the study will be recorded in the eCRF. Exceptions 
are made for medications administered for the purpose of the aneurysm-securing 
procedure, either intra or peri-procedurally (e.g., anesthetics), which do not need to be 
entered into the eCRF. All medications administered after randomization and up to 
24 hours post-study drug discontinuation will also be recorded in the eCRF. Additionally,  
• forbidden medication/therapy are to be recorded from hospital admission until Day 14 
post-study drug initiation,  
• rescue medication must be recorded until Week 12 post-aSAH,  


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• medications administered for serious AEs (SAEs) are to be recorded from study drug 
start until EOS.  
• medications administered for AEs/SAEs related to a protocol-mandated procedure 
must be recorded from ICF signature up until EOS.  
The generic name, start/end dates and times of administration, route, dose regimen, and 
indication will be recorded. 
The following drug and non-drug therapies should be recorded in the eCRF if they were 
performed at any time from randomization up to hospital discharge and from hospital 
discharge up to Week 12: 
• ICP monitoring (with start and end dates). 
• Ventricular drainage (with start and end dates). 
• Shunt (ventriculoperitoneal or ventriculoatrial). 
• Sub/epidural hematoma evacuation. 
• Lumbar drainage (with start and end dates). 
• Mechanical ventilation (with start and end dates). 
• Tracheostomy. 
• Cerebral angioplasty (with start and end dates/times). 
• Other local rescue therapies for cerebral vasospasm (e.g., intrathecal, intra-cisternal, 
intra-ventricular vasodilators, intra-aortic balloon counter-pulsation) with start and end 
dates/times. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI, from 
study drug initiation up to 14 days post-study drug initiation. 
Clinical deterioration due to DCI is defined as a worsening of at least 2 points compared 
to the reference score, on the modified GCS (mGCS) or the abbreviated National Institutes 
of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which cannot be entirely 
attributed to causes other than cerebral vasospasm. It is centrally adjudicated by the CEC 
based on a written charter and review of clinical data, case narratives, angiograms and CT 
scans.  
The initial reference scores to which subsequent scores are compared is assessed within 
30 minutes prior to study drug start. Thereafter, the reference scores will depend on the 
clinical evolution of the subject. After sustained improvements or worsenings in clinical 


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status, the new reference scores will be recalibrated to reflect the best mGCS and aNIHSS 
scores attained by the subject immediately prior to an episode of clinical deterioration.  
Subjects who die between study drug start up to and including 14 days post-study drug 
initiation will be considered as presenting with clinical deterioration due to vasospasm. 
Subjects who cannot be evaluated for neurological status at any time during this same 
period will be considered as presenting with clinical deterioration due to vasospasm if 
either rescue therapy was administered for a relevant vasospasm or the reason for not being 
evaluable is vasospasm-related as confirmed by the CEC. Otherwise, these subjects will 
not be considered as presenting with clinical deterioration due to vasospasm.  
Subjects who are discharged from the study site prior to Day 14 post-study drug initiation 
will have less than 14 days of neurological scales assessments performed. These subjects 
will have a follow-up visit or telephone call, covering their clinical status between 
discharge and Day 14 post-study drug start, as described in Section 7.2.2.2.1. This 
follow‑up data for subjects who were enrolled under earlier protocol versions and 
discharged prior to Day 14 will also be collected retrospectively. If this follow-up reveals 
that the subject was re-hospitalized or transferred to another facility, and DCI cannot be 
ruled out as a primary or contributing cause, the subject will be considered as meeting the 
primary endpoint.  
If a subject has less than 14 days of neurological scales available and there is an absence 
of follow-up information (including subjects withdrawn from the study during the 
observation period) the primary endpoint will be assessed based on the totality of available 
clinical data. 
Further details are provided in the CEC charter. 
6.1.2 Secondary efficacy endpoints 
6.1.2.1 Main secondary endpoint 
The main secondary endpoint is the occurrence of clinically relevant cerebral infarction* 
at Day 16 post-study drug initiation defined as:  
• all-cause cerebral infarction ≥ 5 cm3 or 
• cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI 
*Cerebral infarction refers to new or worsened infarcts and is determined by central radiology review 
comparing the total volume of infarcts on the CT scan performed 16 days after study drug initiation with the 
total volume on the CT scan performed just prior to randomization. If the CT scan cannot be performed on 
Day 16, then it is acceptable for the CT to be performed within the 7 days following Day 16. If a subject is 
discharged from the hospital prior to Day 16, the CT scan is performed on the day of hospital discharge. 
Clinical deterioration due to DCI and cerebral infarctions ≥ 5 cm3 are confirmed by the CEC. Cerebral 
infarctions < 5 cm3 in subjects with clinical deterioration due to DCI are derived from both the CEC data 
(primary endpoint) and IRC data (for infarct size). 


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6.1.2.2 Other secondary endpoints 
The other secondary endpoints are:  
• the long-term clinical outcome assessed by the mRS at Week 12 post-aSAH, 
dichotomized into poor outcome (score ≥ 3) and good outcome (score < 3) and  
• the long-term clinical outcome assessed by the Glasgow Outcome Scale Extended 
(GOSE) at Week 12 post-aSAH, dichotomized into poor outcome (score ≤ 4) and 
good outcome (score > 4). 
6.1.3 Exploratory efficacy endpoints 
6.1.3.1 Cognition endpoints 
• Cognitive status, as assessed by the change from baseline to 14 days post-study drug 
initiation on the Montreal Cognitive Assessment (MoCA), for those subjects that have 
a MoCA at baseline and at 14 days post-study drug initiation.  
• Cognitive status, as assessed by the change from baseline to Week 12 post-aSAH on 
the MoCA, for those subjects that have a MoCA at baseline and at Week 12 post-aSAH. 
• Cognitive status as assessed by the change in MoCA from 14 days post-study drug 
initiation to Week 12 post-aSAH, for those subjects that have a MoCA at 14 days 
post-study drug initiation and at Week 12 post-aSAH. 
• Cognitive status as assessed by the MoCA at 14 days post-study drug initiation and at 
Week 12 post-aSAH. 
6.1.3.2 Other efficacy endpoints 
• 
Number of episodes of clinical deterioration due to DCI from study drug initiation up 
to 14 days post-study drug initiation, as adjudicated by the CEC. 
• 
Occurrence of all-cause new or worsened cerebral infarction ≥ 5 cm3 in total volume, 
as adjudicated by the CEC. 
6.2 Safety endpoints 
• Occurrence of treatment-emergent AEs (TEAEs) up to 24 hours after study drug 
discontinuation. 
• Occurrence of serious TEAEs up to 24 hours after study drug discontinuation.  
• Occurrence of TEAEs leading to premature discontinuation of study drug. 
• Occurrence of death (all causes) up to Week 24 post-aSAH. 
• Occurrence of TEAEs of specific interest (i.e., lung complications, hypotension, 
anemia, cerebral hemorrhage, cerebral edema, fluid retention, hepatic disorders, 
tachyarrhythmia) up to 24 hours after study drug discontinuation. 
• Occurrence of rescue therapy-specific AEs up to hospital discharge (or Week 12, 
whichever is earlier). 


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• Occurrence of treatment-emergent marked laboratory abnormalities up to 24 hours 
after study drug discontinuation, and changes from baseline to end of study drug 
administration for selected centrally assessed laboratory parameters. 
6.3 Quality of Life endpoints 
• Generic QoL as measured by the EQ-5D at Week 12 and Week 24 post-aSAH and the 
Oxford Participation and Activities Questionnaire (Ox-PAQ) at Week 12 post-aSAH.  
• Generic QoL as measured by the change in EQ-5D index score and visual analog scale 
from 12 to 24 weeks post-aSAH, for those subjects that have an EQ-5D both at 
Week 12 and at Week 24 post-aSAH. 
• Disease-specific QoL as measured by the Stroke Specific Quality of Life (SS-QOL) at 
Week 12 post-aSAH. 
6.4 Pharmaco-economic endpoints 
• Number and type of episodes of rescue therapy, from randomization up to hospital 
discharge and from hospital discharge up to Week 12 post-aSAH. 
• Number and type of specific (pre-specified) medical treatments and therapies from 
randomization up to hospital discharge and from hospital discharge up to Week 12. 
• Length of initial and total ICU stay, length of total hospitalization, and duration in 
different hospital/institutional care units, from randomization up to hospital discharge 
and from hospital discharge until Week 12. 
• Intensity of rehabilitation care up to Week 12 post-aSAH. 
• First post-hospital discharge location.  
• Duration of home care support post-initial hospital discharge. 
• Employment status at Week 24 post-aSAH. 
6.5 Biomarker endpoints 
• Area under the plasma concentration-time curve (AUC) of S100b protein from baseline 
to Day 10 post-study drug initiation. 
• AUC of S100b protein from baseline to Day 14 post-study drug initiation. 
6.6 Rationale for primary and secondary efficacy endpoints 
6.6.1 Rationale for the choice of the primary efficacy endpoint 
The primary efficacy endpoint for the proposed Phase 3 study is the occurrence of clinical 
deterioration due to DCI from study drug initiation up to 14 days post-study drug initiation. 
It is defined as a sustained worsening in neurological status that cannot be entirely 
attributed to causes other than cerebral vasospasm as described in Section 6.1.1. 
The primary endpoint as defined captures the most relevant clinical manifestations of 
post-aSAH cerebral ischemia that can be prevented by an anti-vasospastic strategy. The 


Clazosentan / ACT-108475 
Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
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Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
poor prognosis of patients who develop clinical deterioration due to DCI and its 
downstream complications are well-established [see Sections 1.1 and 1.5]. Therefore, 
showing a significant reduction in the incidence of clinical deterioration due to DCI, 
supported by clinically relevant effects on the secondary and exploratory endpoints, will 
altogether demonstrate the clinically meaningful benefit of clazosentan in this disease 
indication. 
The assessment period for the primary endpoint extends until 14 days after the initiation of 
treatment, thus covering the treatment period, and corresponding to the period during 
which DCI is most likely to occur. 
The proposed primary endpoint definition is aligned with the recommendations of an 
international multi-disciplinary aSAH research group who proposes to standardize the 
definition of clinical deterioration due to DCI as the occurrence of focal neurological 
impairment or a decrease of at least 2 points on the GCS lasting for at least 1 hour 
[Vergouwen 2010]. The extension of the duration of the deterioration to 2 hours in the 
REACT protocol will exclude transient fluctuations in clinical status and thus increase the 
robustness of the endpoint definition. 
Long-term clinical outcome has not been chosen as the primary efficacy endpoint. At the 
time the nimodipine trials were conducted, early ischemic complications were largely the 
first cause of poor outcome and the frequency of brain infarct was in excess of 40–50% 
post-aSAH [Petruk 1988, Ohman 1991]. Today, the vasospasm-related infarct rate has 
considerably decreased (13.3 and 13.2% in the placebo groups of the CONSCIOUS-2 and 
CONSCIOUS-3 studies, respectively), hence reducing the proportion of poor outcome due 
to vasospasm-related infarcts. It is estimated that today, the direct contribution of 
vasospasm does not exceed one-third of the overall rate of unfavorable outcome, the 
remainder of poor outcome being related to the primary injury and iatrogenic and medical 
complications inherent to the underlying condition. Hence, testing a treatment which only 
impacts vasospasm would result, with the GOSE as primary endpoint, in a sample size of 
the study exceeding that which would be feasible given the rarity of the disease 
[Kreiter 2009]. 
6.6.2 Rationale for the choice of secondary efficacy endpoints 
6.6.2.1 Occurrence of clinically relevant cerebral infarction at Day 16 post-study drug 
initiation defined as: all-cause cerebral infarction ≥ 5 cm3 or cerebral 
infarction < 5 cm3 in subjects with clinical deterioration due to DCI 
Among the known complications of aSAH, the occurrence of cerebral infarction on 
neuro-imaging has been repeatedly shown to be the strongest predictor of poor long-term 
clinical outcome [Frontera 2009, Kreiter 2009, Vergouwen 2010]. The clinical relevance 
of this secondary efficacy endpoint is therefore high, and cerebral infarction was even 
suggested as a primary endpoint in recent international recommendations for aSAH trials 
[Vergouwen 2010]. 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
Final Version 7 
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Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
A post-hoc analysis of the data from the CONSCIOUS-2 and CONSCIOUS-3 studies 
shows that infarcts with a total cumulative volume ≥ 5 cm3 are mostly related to vasospasm 
and have a high association with poor clinical outcome at 3 months, as compared to those 
with a cumulative volume less than 5 cm3 [Roux 2021]. Therefore, the original secondary 
endpoint definition (all-cause new or worsened cerebral infarction of a total volume 
≥ 5 cm3) only included those infarcts ≥ 5 cm3 in order to set a meaningful cut-off for infarct 
volume when considering all infarcts irrespective of cause. Since the determination of 
underlying infarct etiology based on CT scan assessment is often challenging, the 5 cm3 
threshold serves as a proxy for vasospasm-relatedness. The endpoint also allowed the 
identification of ischemic events that are not detectable on clinical examination or that 
develop in patients who cannot be evaluated neurologically (e.g., due to sedation or very 
poor clinical status). However, routine blinded monitoring of the event rate during the 
REACT study revealed a lower-than-expected incidence of infarcts ≥ 5 cm3, resulting in 
insufficient power to detect a treatment effect. This led to an expansion of the endpoint 
definition to include smaller but clinically relevant infarcts. 
Although the infarcts < 5 cm3 have a lower association with vasospasm and poor outcome, 
their vasospastic origin and their contribution to poor outcome cannot be excluded. The 
presence of these smaller infarcts may lead to important clinical manifestations 
[Weidauer 2007, Biesbroek 2017]. It would therefore be desirable to identify, from the 
smaller infarcts, those that are clinically relevant, rather than including all infarcts < 5 cm3. 
Indeed, it has been observed from the CONSCIOUS-1 [Macdonald 2008] and the recently 
completed clazosentan Japanese Phase 3 studies [in press], that including all infarcts 
irrespective of size and etiology results in a dilution of the treatment effect. Therefore, the 
modified endpoint definition includes those smaller infarcts which occur in subjects who 
deteriorate due to DCI. 
Despite being correlated with the primary efficacy endpoint, the main secondary endpoint 
goes beyond clinical symptoms since deterioration due to DCI does not always result in 
the development of cerebral infarction. Conversely, cerebral infarction may be observed 
on a CT scan in the absence of clinical symptoms in up to 20% of aSAH patients 
[Rabinstein 2005, Schmidt 2008].  
The assessment of this endpoint at Day 16 post-study drug initiation will allow for the 
detection of infarcts that may be the consequence of cerebral ischemia that occur on Day 14 
(primary endpoint evaluation is up to Day 14). 
6.6.2.2 Modified Rankin Scale and Glasgow Outcome Scale Extended 
Since the detection of a treatment effect on long-term clinical outcome using an 
anti-vasospastic drug would require a sample size exceeding several thousand subjects 
[Kreiter 2009, Rosengart 2007], it is not expected that any beneficial effect of clazosentan 
on the mRS or the GOSE be demonstrable with the current feasibility-limited sample size. 
However, the absence of a negative trend on these assessments will be an important part of 
the overall benefit-risk assessment of clazosentan in subjects post-aSAH. This justifies the 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
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Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
use of mRS and GOSE as other secondary endpoints. The MRS is included in the statistical 
hierarchical testing strategy, just before the GOSE. Results from the Japanese Phase 3 
studies (AC-054-305 and 306) show that the mRS can slightly better discriminate the 
treatment effect of clazosentan on clinical outcome at Week 12 post-aSAH, compared to 
the GOSE. This suggests a better sensitivity of the mRS, despite the similarity of the two 
instruments. The mRS has recently been recommended over the GOSE as the preferred 
scale for measuring the long-term clinical outcome of SAH by the international clinical 
experts of the SAH common data elements working group [Suarez 2019].    
Prevention of vasospasm and DCI post-aSAH may be demonstrated to have an impact on 
long-term clinical outcome when confounding factors, on which an anti-vasospastic drug 
like clazosentan cannot have an effect, have been removed. In CONSCIOUS-3, when 
subjects with neurological impairment, either due to the initial bleed or the aneurysm-repair 
procedure are removed, a positive effect of clazosentan on long-term outcome is observed. 
This observation suggests that in this population, secondary neurological deterioration 
leading to poor outcome is mainly driven by vasospasm. Hence, an exploratory analysis 
will assess the effect of clazosentan on the mRS and GOSE at Week 12 post-aSAH, in the 
subset of subjects who fully recovered neurologically immediately prior to study drug start. 
7 
STUDY PERIODS, VISITS AND ASSESSMENTS 
7.1 Study periods and “visits” 
The study periods and “visits” with their respective time windows are listed in the visit and 
assessment schedules.  
Table 1 corresponds to the high-risk prevention group and Table 2 to the early treatment 
group. 
Note: Table 2 is provided for the early treatment group although recruitment into this group 
was discontinued from protocol version 6 onwards. 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
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Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
Visit and assessment schedules 
Table 1 
Visit and assessment schedule for subjects in the high-risk prevention group 
PERIOD 
 
Hospital 
admission 
SCREENING 
Period 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety FU  
Period 
Extended FU Period 
(From end of 24 h safety FU Period 
until EOS) 
TREATMENT Period 
(min. 10, max. 14 days of treatment)  
Timing / assessment 
within 96 hours post-aSAH 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS)19 
From ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start Daily in ICU8  
During observation 
period8 
Worsening of 
≥ 2 points on mGCS / 
aNIHSS8 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical history  
 
X 
X 
 
 
 
 
 
 
Incl./Excl. criteria 
 
X 
 
 
 
 
 
 
 
Height, weight 
 
X 
 
 
 
 
 
 
 
Vital signs (BP, HR, ICP1, 
CVP1) 
 
 
X  
(within 60 min) 
q6h 
(± 1 h) 
q6h (± 1 h)  
(every 12 h if not in 
ICU) 
 
 
 
 
Body temperature 
 
 
X  
(within 60 min) 
X  
(every 12 h ± 1 h)  
 
 
 
 
Fluid balance (24 h)16 
 
 
X 
X 
 
 
 
 
 
ECG parameters 
 
 
X 
(within 60 min) 
X9 
X (within 2 h 
post-SD stop) 
 
 
Laboratory tests  
(local [l]/ central [c]) 
 
X (l) 
X (c)  
(within 60 min) 
X10 (c) (EOD for 14 days)  
X (l) / SpO2 
X10 (c) (within 2 h 
post-SD stop)  
 
 
Biomarker  
 
 
X (c)  
(within 60 min) 
X (c) (EOD for 14 days) 
X (c) if CNS cause 
X (c) (within 2 h 
post-SD stop)  
 
 
Pregnancy test  
 
X (serum, (l)) 
 
 
 
 
 
X (urine) 
 
Concomitant 
medications18 
X  
 
X 
Non-drug treatments / 
interventions 
 
 
X 
X 
WFNS  
X2 
X, X3 
 
 
 
 
 
 
 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
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Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
PERIOD 
 
Hospital 
admission 
SCREENING 
Period 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety FU  
Period 
Extended FU Period 
(From end of 24 h safety FU Period 
until EOS) 
TREATMENT Period 
(min. 10, max. 14 days of treatment)  
Timing / assessment 
within 96 hours post-aSAH 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS)19 
From ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start Daily in ICU8  
During observation 
period8 
Worsening of 
≥ 2 points on mGCS / 
aNIHSS8 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
Total GCS 
X2 
X, X3 
 
 
 
 
 
 
 
mGCS/aNIHSS 
 
 
X  
(within 30 min) 
q6h11 
(± 1 h) 
X12 
(± 1 h) 
X  
(hourly ± 15 min for 
first 2 h) 
 
 
 
Angiogram  
(DSA or CTA) 
X4 
X  
(local standard 
of care, not 
assessed 
centrally) 
 
 
 
X  
(if CNS cause) 
 
 
 
CT scan 
X4 
X5 
 
 
 
X  
(if CNS cause) 
X13 (16 days post-
SD start) 
 
 
Subject narrative 
 
 
 
 
 
X (14 days post-SD 
start) 
 
 
 
MoCA6 
 
X7 
 
X (14 ± 1 day post-SD 
start) 17 
 
 
X 
 
GOSE 
 
 
 
 
 
 
 
X 
 
SS-QOL, Ox-PAQ  
 
 
 
 
 
 
 
X 
 
EQ-5D 
 
 
 
 
 
 
 
 
X 
X 
Study drug administration 
 
 
 
X 
X 
 
 
 
 
 
Adverse events14 
 
X 
 
X 
Serious adverse events15 
 
X 
X 
Pharmaco-economic 
assessments 
 
 
X 
 
X 
 
Employment status 
 
 
 
 
 
X 


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Protocol ID-054-304, REACT 
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EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
1. ICP/CVP will be measured and recorded for those subjects with ICP and/or CVP monitoring in place. 
2. If the subject was transferred from another hospital, the GCS score and WFNS grade will correspond to the assessments made at the referral hospital, unless these were not done or not reliable. 
3. Two assessments: post aneurysm-securing procedure and prior to randomization. 
4. If performed at a referral hospital, is of acceptable quality, and is available in digital format at the investigational site at the time of screening, does not need to be repeated. 
5. This CT scan is to be performed at least 8 hours after the aneurysm-securing procedure and within 24 hours prior to randomization. 
6. Only performed if subject is GCS ≥ 13 and extubated (if applicable). 
7. As soon as possible after recovering from the aneurysm-securing procedure and prior to SD start.  
8. If there is a worsening of at least 2 points in the mGCS and/or the aNIHSS the assessments in the “worsening” column must be performed on top of the regularly scheduled assessments. The mGCS 
and the aNIHSS must be repeated hourly for at least the first 2 hours after a 2-point worsening. If the deterioration is believed to be of CNS origin, a cerebral angiogram and a cerebral CT scan must 
be performed within 6 hours of the start of the symptoms and submitted for central review and a blood sample for S100b protein must be drawn within 1 hour of the confirmation of the neurological 
deterioration episode or no later than 3 hours from the initial worsening. Local lab tests should be obtained as close as possible to the time of the clinical worsening (max. 1 hour after time of confirmed 
worsening) [See Section 7.2.2.2.1 for details]. 
9. QT, QRS, PR, RR intervals, and HR will be measured and recorded in the eCRF if subject experiences an AE related to cardiac rhythm abnormalities [see Section 7.2.3.7]. 
10. Any clinically significant laboratory values must be reported as an AE/SAE as appropriate and those still abnormal at the time of the EOS assessment will be followed up based on local routine standard 
of care. A local laboratory may be requested by the sponsor to document the event and its resolution, and the results recorded in the eCRF [see Section 7.2.4.1]. 
11. At least once per day for subjects that require uninterrupted continuous sedation. 
12. After the end of the study drug infusion, the mGCS and aNIHSS will continue to be assessed every 6 hours if the subject is still in the ICU (or equivalent ward), until 14 days after study drug initiation. 
They will be assessed at least once per day if the subject requires continuous uninterrupted sedation. If the subject is no longer in the ICU (i.e., has been sent to a regular/general ward), the mGCS and 
aNIHSS will be assessed at least once every 12 hours (± 1 h) until 14 days after study drug initiation. In the unavoidable situation where the subject is discharged from the study site before completing 
the observation period, their clinical status must be followed up to cover the period between discharge and Day 14 post-study drug start. The follow-up should be performed on Day 14 post-study drug 
initiation or as soon as possible after. This follow-up is not required if the subject was discharged on Day 13 and there is at least one set of neurological assessment scales available on this day. 
13. If the CT scan cannot be performed on the 16th day post-SD start, then it is acceptable if the CT scan is performed up to 7 days after Day 16. The CT scan will be performed on the day of hospital 
discharge for those subjects who are discharged from the hospital prior to 16 days after study drug start. If no CT scan is available at hospital discharge, the last CT scan performed prior to discharge 
may be used for this assessment. For further details see Section 7.2.2.4.4. 
14. All AEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other AEs are to be reported from SD initiation until 24 hours 
post-permanent SD discontinuation. 
15. All SAEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other SAEs are to be reported from SD initiation until EOS. Waived 
SAEs do not require reporting to the sponsor’s Drug Safety department within 24 hours of the knowledge of its occurrence [see Section 9.1.3]. 
16. Applicable during study drug administration only. Balance is captured if a urine catheter is present. Otherwise, 24-hour fluid intake will be measured and recorded. 
17. This MoCA will be performed on the day of hospital discharge for those subjects who are discharged from the hospital prior to 14 days after study drug start. 
18. For details on the concomitant medication recording refer to Section 5.2.5. 
19. The EOS visit is conducted remotely as a telephone interview. 
AE = adverse event; aNIHSS = abbreviated National Institutes of Health Stroke Scale; aSAH = aneurysmal subarachnoid hemorrhage; BP = blood pressure; CNS = central nervous system; CT = computerized 
tomography; CTA = computerized tomography angiography; CVP = central venous pressure; DSA = digital subtraction angiography; ECG = electrocardiogram; eCRF = electronic case report form; EOD 
= every other day; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; GCS = Glasgow Coma Scale; GOSE = Glasgow Outcome Scale Extended; HR = heart rate; ICF = informed consent 
form; ICP = intracranial pressure; ICU = intensive care unit; mGCS = modified Glasgow Coma Scale; MoCA = Montreal Cognitive Assessment; Ox-PAQ = Oxford Participation and Activities 
Questionnaire; SAE = serious adverse event; SD = study drug; SpO2 = peripheral capillary oxygen saturation; SS-QOL = Stroke Specific Quality of Life; WFNS = World Federation of Neurological 
Societies. 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
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EudraCT 2018-000241-39 
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Table 2 
Visit and assessment schedule for subjects in the early treatment group (recruitment into this group was discontinued from protocol version 
6 onwards) 
PERIOD 
Hospital 
Admission  
SCREENING 
Period 
 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety 
FU Period  
Extended FU Period 
(From end of 24 h safety FU period 
until EOS) 
TREATMENT Period 
(min. 6, max. 14 days of treatment) 
Timing / assessment 
until max. Day 14 
post-aSAH 
within 24 h of pre-
randomization 
angiogram5 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS) 21 
from ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start 
Daily 
in ICU9  
During observation 
period9 
Worsening of  
≥ 2 points on 
mGCS / 
aNIHSS9 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical history  
 
X 
X 
 
 
 
 
 
 
Incl./Excl. criteria 
 
X 
 
 
 
 
 
 
 
Height, weight 
 
X 
 
 
 
 
 
 
 
Vital signs (BP, HR, ICP1, 
CVP1) 
 
 
X  
(within 60 min) 
q6h 
(± 1 h) 
q6h (± 1 h) 
(every 12 h if not in 
ICU) 
 
 
 
 
Body temperature 
 
 
X  
(within 60 min) 
X  
(every 12 h ± 1 h) 
 
 
 
 
Fluid balance (24 h)18 
 
 
X 
X 
 
 
 
 
 
ECG parameters 
 
 
X  
(within 60 min) 
X10 
X (within 2 h 
post-SD stop) 
 
 
Laboratory tests (local [l]/ 
central [c]) 
 
X (l) 
X (c)  
(within 60 min) 
X11 (c)  
(EOD for 14 days)  
X (l) /SpO2 
X11 (c) (within 2 h 
post-SD stop) 
 
 
Biomarker  
 
 
X (c) (within 60 
min) 
X (c) 
(EOD for 14 days)  
X (c) 
(if CNS cause) 
X (c) (within 2 h 
post-SD stop) 
 
 
Pregnancy test  
 
X (serum, (l)) 
 
 
 
 
 
X (urine) 
 
Concomitant medications20 
X  
X 
Non-drug treatments / 
interventions 
 
 
X 
X 
WFNS  
X2 
X, X3 
 
 
 
 
 
 
 
Total GCS 
X2 
X, X3 
 
 
 
 
 
 
 


Clazosentan / ACT-108475 
Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
Final Version 7 
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Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
PERIOD 
Hospital 
Admission  
SCREENING 
Period 
 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety 
FU Period  
Extended FU Period 
(From end of 24 h safety FU period 
until EOS) 
TREATMENT Period 
(min. 6, max. 14 days of treatment) 
Timing / assessment 
until max. Day 14 
post-aSAH 
within 24 h of pre-
randomization 
angiogram5 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS) 21 
from ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start 
Daily 
in ICU9  
During observation 
period9 
Worsening of  
≥ 2 points on 
mGCS / 
aNIHSS9 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
mGCS/aNIHSS 
 
 
X  
(within 30 min) 
q6h12 
(± 1 h) 
X13 
(± 1 h) 
X  
(hourly ± 15 min 
for first 2 h) 
 
 
 
Angiogram  
(DSA or CTA) 
X4 
X17  
X5 
 
 
 
X 
(if CNS cause) 
 
 
 
CT scan 
X4 
X6 
 
 
 
X 
(if CNS cause) 
X14 (16 days 
post-SD start) 
 
 
Subject narrative 
 
 
 
 
 
X (14 days 
post-SD start) 
 
 
 
MoCA7 
 
X8 
 
X (14 ± 1 day 
post-SD start) 19 
 
 
X 
 
GOSE 
 
 
 
 
 
 
 
X 
 
SS-QOL, Ox-PAQ 
 
 
 
 
 
 
 
X 
 
EQ-5D 
 
 
 
 
 
 
 
 
X 
X 
Study drug administration 
 
 
 
X 
X 
 
 
 
 
 
Adverse events15 
 
X 
 
X 
Serious adverse events16 
 
X 
X 
Pharmaco-economic 
assessments 
 
 
X 
 
X 
 
Employment status 
 
 
 
 
 
X 
1. ICP/CVP will be measured and recorded for those subjects with ICP and/or CVP monitoring in place. 
2. If the subject was transferred from another hospital, the GCS score and WFNS grade will correspond to the assessments made at the referral hospital, unless these were not done or unreliable. 
3. Two assessments: post aneurysm-securing procedure and prior to randomization. 
4.  If performed at a referral hospital, is of acceptable quality, and is available in digital format at the investigational site at the time of screening, does not need to be repeated. 
5. The DSA or CTA which was performed according to local routine standard of care (preferably between Day 7 and 11 post-aSAH) and used to diagnose and document the vasospasm will be collected. 


Clazosentan / ACT-108475 
Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
Final Version 7 
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Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
6. This CT scan is to be performed at least 8 hours after the aneurysm-securing procedure and within 24 hours prior to randomization. 
7. Only performed if subject is GCS ≥ 13 and extubated (if applicable). 
8. As soon as possible after recovering from the aneurysm-securing procedure and prior to SD start.  
9. If there is a worsening of at least 2 points in the mGCS and/or the aNIHSS the assessments in the “worsening” column must be performed on top of the regularly scheduled assessments. The mGCS 
and the aNIHSS must be repeated hourly for at least the first 2 hours after a 2-point worsening. If the deterioration is believed to be of CNS origin, a cerebral angiogram and a cerebral CT scan must 
be performed within 6 hours of the start of the symptoms and submitted for central review and a blood sample for S100b protein must be drawn within 1 hour of the confirmation of the neurological 
deterioration episode or no later than 3 hours from the initial worsening. Local lab tests should be obtained as close as possible to the time of the clinical worsening (max. 1 hour after time of confirmed 
worsening) [see Section 7.2.2.2.1 for details]. 
10. QT, QRS, PR, RR intervals, and HR will be measured and recorded in the eCRF if subject experiences an AE related to cardiac rhythm abnormalities [see Section 7.2.3.7]. 
11. Any clinically significant laboratory values must be reported as an AE/SAE as appropriate and those still abnormal at the time of the EOS assessment will be followed up based on local routine standard 
of care. A local laboratory may be requested by the sponsor to document the event and its resolution, and the results recorded in the eCRF [see Section 7.2.4.1]. 
12. At least once per day for subjects that require uninterrupted continuous sedation. 
13. After the end of the study drug infusion, the mGCS and aNIHSS will continue to be assessed every 6 hours if the subject is still in the ICU (or equivalent ward), until 14 days after study drug initiation. 
They will be assessed at least once per day if the subject requires continuous uninterrupted sedation. If the subject is no longer in the ICU (i.e., has been sent to a regular/general ward), the mGCS and 
aNIHSS will be assessed at least once every 12 hours (± 1 h) until 14 days after study drug initiation. In the unavoidable situation where the subject is discharged from the study site before completing 
the observation period, their clinical status must be followed up to cover the period between discharge and Day 14 post-study drug start. The follow-up should be performed on Day 14 post-study drug 
initiation or as soon as possible after. This follow-up is not required if the subject was discharged on Day 13 and there is at least one set of neurological assessment scales available on this day.14. If 
the CT scan cannot be performed on the 16th day post-SD start, then it is acceptable if the CT scan is performed up to 7 days after Day 16. The CT scan will be performed on the day of hospital 
discharge for those subjects who are discharged from the hospital prior to 16 days after study drug start. If no CT scan is available at hospital discharge, the last CT scan performed prior to discharge 
may be used for this assessment. For further details see Section 7.2.2.4.4. 
15. All AEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other AEs are to be reported from SD initiation until 24 hours 
post-permanent SD discontinuation. 
16. All SAEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other SAEs are to be reported from SD initiation until EOS. Waived 
SAEs do not require reporting to the sponsor’s Drug Safety department within 24 hours of the knowledge of its occurrence [see Section 9.1.3]. 
17. Angiogram performed as per local standard of care to confirm successful aneurysm-securing procedure. Angiogram not assessed centrally. 
18. Applicable during study drug administration only. Balance is captured if a urine catheter is present. Otherwise, 24-hour fluid intake will be measured and recorded. 
19. This MoCA will be performed on the day of hospital discharge for those subjects who are discharged from the hospital prior to 14 days after study drug start. 
20. For details on the concomitant medication recording refer to Section 5.2.5. 
21. The EOS visit is conducted remotely as a telephone interview. 
AE= adverse event; aNIHSS = abbreviated National Institutes of Health Stroke Scale; aSAH = aneurysmal subarachnoid hemorrhage; BP = blood pressure; CNS = central nervous system; CT = computerized 
tomography; CTA = computerized tomography angiography; CVP = central venous pressure; DSA = digital subtraction angiography; ECG = electrocardiogram; eCRF = electronic case report form; EOD 
= every other day; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; GCS = Glasgow Coma Scale; GOSE = Glasgow Outcome Scale Extended; HR = heart rate; ICF = informed consent 
form; ICP = intracranial pressure; ICU = intensive care unit; mGCS = modified Glasgow Coma Scale; MoCA = Montreal Cognitive Assessment; Ox-PAQ = Oxford Participation and Activities 
Questionnaire; SAE = serious adverse event; SD = study drug; SpO2 = peripheral capillary oxygen saturation; SS-QOL = Stroke Specific Quality of Life; WFNS = World Federation of Neurological 
Societies. 


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7.1.1 Screening/re-screening 
7.1.1.1 Screening period 
The screening period starts with the signature of the ICF see Section 12.3 for informed 
consent procedure, and ends when the subject is either randomized into the study or 
screen-failed.  
During this period, the subject is evaluated for suitability for the study based on the 
inclusion and exclusion criteria. The subjects who agree to participate in the study, and/or 
their proxy (i.e., a family member, legal representative, third party as applicable depending 
on local regulations), and the investigator/delegate must sign the ICF prior to any 
study-related assessment or procedure. These evaluations can take place on different days 
during the screening period. For a description of all assessments performed during the 
treatment period, refer to Table 1 and Section 7.2. 
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, and the ICF was also signed by the investigator or delegate, 
prior to any study-specific procedures being performed. If a study-specific procedure or 
assessment has already been performed as part of local standard practice prior to the 
consent, this information, provided it fulfills study requirements, may be used for study 
purposes and does not have to be repeated.  
After the ICF has been signed, the investigator/delegate contacts the IRT system to allocate 
a subject number to the subject. Subjects who have signed the ICF when the enrollment 
target has been met may still be randomized into the study. 
7.1.1.2 Re-screening 
Subjects who did not meet the criteria for participation in the study (i.e., screen failure) are 
not allowed to be re-screened.  
Since the screening period may extend over more than one day, any potentially transient 
condition during screening that may exclude a subject from the study (e.g., total bilirubin 
> 2 × the upper limit of normal) may be re-assessed at a later time point prior to 
randomization, to check for resolution or improvement. In this situation, the subject is kept 
in screening until the re-evaluation and is not immediately screen-failed. 
7.1.1.3 Randomization without subsequent start of study drug 
Subjects who are randomized but for whom study drug is never initiated (e.g., due to a 
sudden deterioration of the clinical status post-randomization), will be withdrawn from the 
study for safety or other reasons, by the investigator, and no further assessments will be 
performed. Imaging (cerebral CT scans and angiograms) that have been performed during 


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the screening period, and which are required according to the protocol, will be submitted 
to the imaging CRO for central review. 
The EOS page of the eCRF must be completed with the reason for withdrawal from the 
study documented. 
7.1.2 Treatment period 
The treatment period starts with the performance of the baseline assessments, after the 
subject has been randomized into the study, and before the initiation of study drug. The 
treatment period covers the entire duration of study drug administration, and the 
corresponding assessments performed during the administration of study drug.  
Treatment duration is dependent on the subject’s individual clinical course and the 
investigator’s judgment on the perceived need to continue the study drug [see 
Section 5.1.3.3.4 for further details].  
For subjects randomized in the high-risk prevention group, treatment will start within 
96 hours following the time of the aneurysm rupture, and be administered where possible, 
for 14 days. For subjects that require early discharge from the ICU (or equivalent), study 
drug must be administered for a minimum of 10 days. This treatment duration covers the 
period when vasospasm is most likely to occur. 
For subjects randomized in the early treatment group*, treatment must begin within 
24 hours of the time of the angiogram documenting the cerebral vasospasm necessary for 
entry into the study. Treatment will be administered for a minimum of 6 days and a 
maximum of 14 days.  
For a description of all assessments performed during the treatment period, refer to Table 1 
and Section 7.2. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
7.1.3 24-hour safety follow-up period 
The 24-hour safety follow-up period starts with the permanent discontinuation of study 
drug and ends 24 hours later. Subjects must not be discharged from the hospital until the 
end of this period. 
New AEs occurring in the 24-hour period starting from the end of study drug 
administration are recorded in the eCRF.  
The EOT assessments are included in this period. These assessments are performed within 
2 hours following the permanent discontinuation of study drug. 


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7.1.4 Observation period for primary endpoint 
The observation period starts with the initiation of study drug infusion and ends on and 
includes Day 14 post-study drug initiation. This period covers the interval over which the 
subject may qualify for the primary endpoint of the study. Neurological scales, vital signs, 
body temperature, and ICP are assessed and central laboratory samples are taken regularly 
irrespective of study drug administration. Subjects must be kept at the investigational site 
until at least Day 14 to ensure the assessments required for evaluation of the primary 
endpoint are performed over the entire observation period. 
Exceptional circumstances may occur, resulting in a hospital discharge prior to Day 14 
post-study drug initiation. In this situation, a follow-up must be performed to collect 
relevant clinical information during the period between the discharge and Day 14, as 
described in Section 7.2.2.2.1. This follow-up also applies to subjects who were enrolled 
under previous protocol versions and who were discharged prior to Day 14. 
7.1.5 Extended follow-up period 
The extended follow-up period starts after the 24-hour safety follow-up period and ends 
with the EOS visit [see Section 7.1.8], occurring 24 weeks after the aSAH.  
Safety follow-up information including new AEs related to protocol-mandated procedures 
and all SAEs and related drug therapies up to EOS will be collected during this period. If 
the subject has already been discharged from hospital or has been transferred to another 
hospital, the most appropriate means will be employed to obtain this information. Safety 
follow-up information includes the follow-up of ongoing AEs. 
7.1.6 Unscheduled visits 
For the purpose of the study, there will be no unscheduled visits. 
7.1.7 Week 12 visit  
This visit occurs 12 weeks after the aSAH for both the high-risk prevention and the early 
treatment* groups. For subjects who prematurely withdraw from the study the pregnancy 
testing due at this visit may occur earlier.  
The Week 12 visit will be conducted face-to-face at the investigational study site at 
Week 12 (84 days ± 7 days) with the subject and/or a proxy/caregiver, as applicable. In the 
event that it is impossible for a subject who is already discharged to return to the 
investigational site for this visit (e.g., due to poor clinical status, distance from hospital), 
all attempts will be made to conduct the visit and applicable assessments by telephone and 
complete the remaining assessments by post [see Table 1 and Table 2]. Depending on local 
regulations, a study staff member from the investigative site may also conduct the Week 12 
visit at the subject’s place of residence. 


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*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
7.1.8 EOS visit (individual subject) 
This visit occurs 24 weeks after the aSAH for both the high-risk prevention and the early 
treatment* groups, and is defined as the last visit performed by an individual subject for 
the study. This visit may occur earlier for subjects who prematurely withdraw from the 
study.  
The EOS visit will be conducted remotely at Week 24 (Day 168 ± 2 weeks) post-aSAH as 
a telephone interview with the subject and/or a proxy/caregiver. If the EOS visit cannot be 
conducted as a telephone interview, the subject and/or a proxy/caregiver will be asked to 
complete the applicable data collection forms and return them by post. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
7.1.9 EOS (study level) 
This time point occurs when the last subject randomized into the study completes his/her 
EOS visit. 
7.2 Study assessments 
The study assessments are listed in the visit and assessment schedule [Table 1].  
The assessments that are mandatory during a visit are marked with an ‘X’.  
All study assessments are performed/administered by the investigator/delegate and are 
recorded in the eCRF, unless otherwise specified. 
If a study-specific procedure or assessment has already been performed as part of local 
standard practice, from hospital admission to the moment informed consent is obtained, it 
may be used for study purposes and does not have to be repeated.  
All QoL questionnaires completed by the subject or proxy, as applicable see 
Section 7.2.5, are entered into the corresponding eCRF form by the investigator/delegate. 
The original paper copies will be filed in the ISF and made available for verification by the 
site monitor. 
During the Week 12 visit, whenever feasible, the following order of assessments is 
preferred: MoCA, GOSE, SS-QOL, Ox-PAQ, EQ-5D. If the subject is unable to return to 
the investigative site for the visit, the GOSE will be administered by telephone interview, 
and the subject will be instructed to complete the paper versions of the QoL questionnaires 
(which were sent to them via post) in the above order, where possible on the same day as 
the telephone interview, after the interview has been completed. If it is not possible to 
complete the questionnaires on the same day as the telephone interview, then they should 


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be completed as close to the day of the interview as possible (before or after the interview). 
Depending on local regulations, a study staff member from the investigative site may also 
conduct the Week 12 visit at the subject’s place of residence. 
The EOS visit at Week 24 will be conducted remotely by telephone. If a subject cannot be 
reached following a reasonable number of attempts, the site will attempt to collect the 
necessary data by post. During the EOS visit, whenever feasible, the following order of 
data collection is preferred: EQ-5D, employment status.  
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available unless the equipment is 
provided by the sponsor. Calibration certificates of other equipment must be available as 
per local requirements. 
Equipment for which calibration certificates (or documentation of regular maintenance) 
are needed: 
• Temperature measurement devices for study treatment storage area and laboratory 
sample storage (e.g., refrigerator, freezer); 
• Study drug infusion pump; 
• Centrifuges for laboratory samples; 
• ECG machine;  
• CT (CTA) scanner; 
• DSA equipment. 
7.2.1 Demographics / baseline disease characteristics 
Demographic and baseline disease characteristic data to be collected on all subjects 
include: age at hospital admission, sex, race, and ethnicity (if allowed in the country), 
height, weight, total GCS score at hospital admission, and WFNS grade at hospital 
admission. The individual components of the GCS (i.e., eye opening, verbal, motor) will 
be recorded in the source documentation. If the subject was transferred from another 
hospital, the GCS score and WFNS grade will correspond to the assessments made at the 
referral hospital. However, if the GCS score and WFNS grades from the referral hospital 
were not done or not evaluable / not reliable (e.g., due to sedation), then the assessments 
performed at the investigational site will be entered in the eCRF and used for study 
purposes. 
Relevant medical history / current medical conditions other than those related to the aSAH 
(e.g., chronic and ongoing acute conditions, serious past conditions) present before 
study‑drug initiation will be recorded in the eCRF. Where possible, main diagnoses and 
not symptoms will be recorded. 


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Specific baseline conditions/symptoms of interest that are related to the aSAH will be 
recorded in the eCRF [see Section 7.2.1.1]. 
7.2.1.1 aSAH history 
Relevant aSAH-related medical history will be captured in the eCRF and includes: 
• Date/time of the aneurysm rupture* 
• Total number of aneurysm(s) coiled or clipped 
• Location of the ruptured aneurysm 
• Location of the repaired aneurysm(s), ruptured and unruptured 
• Aneurysm-securing procedure(s) performed 
• Start date and end date and time of aneurysm-securing procedure(s)  
• Largest diameter of the ruptured aneurysm (mm) 
• Complications of the aneurysm-securing procedure which may include, but are not 
limited to the following: 
– Intracranial hemorrhage (including aneurysm rupture during procedure), 
intraoperative cerebral artery thrombosis, cardiac arrest, seizure, intracranial 
hypertension, brain edema or swelling, cerebral infarction/ischemia, cerebral 
vasospasm, other coiling complications, other surgical complications.  
• Previous aSAH (yes/no) 
*Date/time of the aneurysm rupture will be estimated based on clinical symptoms 
experienced by the subject. In general, consider the date/time of the rupture to correspond 
to the date/time of the major headache which resulted in the hospital admission. Do not 
consider minor preceding headaches (sentinel headaches, warning leaks). If the subject was 
found unconscious, then the date/time of the aneurysm rupture corresponds to the date/time 
when the subject was last seen conscious.  
7.2.1.2 Data to be collected for screening failure subjects 
A minimum set of screening failure information is required to ensure transparent reporting 
of screening failure subjects. 
For subjects who failed screening, the following data will be recorded in the eCRF: 
• Age (at hospital admission), sex, race, and ethnicity (if allowed in the country) 
• WFNS grade at hospital admission 
• Type of aneurysm-securing procedure 
• Inclusion criteria not met and/or exclusion criteria met 
• Date and time of informed consent 


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• Whether the subject was subsequently randomized 
• AEs and SAEs related to a study-mandated procedure 
7.2.2 Efficacy assessments 
7.2.2.1 Neurological assessment scales 
All neurological assessments required for the study, starting from those performed to 
determine study eligibility just prior to randomization, including the baseline assessments 
(prior to the start of study drug), and those performed until the end of the observation period 
for the primary endpoint (i.e., until Day 14 post-study drug initiation), will be performed 
by study staff specifically trained and certified to perform these assessments for the purpose 
of the study. The neurological assessments performed at hospital admission and post 
aneurysm-securing procedure may be performed according to local standard of care, as the 
subject will, in most cases, not yet be included in the study (i.e., they will be performed 
prior to signature of the ICF). The GCS assessments for the purpose of assessing the 
subject’s ability to perform the MoCAs may be performed according to routine standard of 
care. 
Certification will be documented by passing a written exam based on content covered in 
the training materials provided by the sponsor. Each investigational site will train and 
certify as many site staff as required to ensure the neurological exams can be performed 
according to the visit and assessment schedule [Table 1 and Table 2] and as described 
below. Study-specific assessments must not be performed by any study staff until 
certification has been obtained. Details on the training and certification may be found in 
the site material provided separately. 
7.2.2.1.1 Glasgow Coma Scale 
The GCS is a measure of level of consciousness and scores range from 3 (worst score) to 
15 (best score). It is composed of three components: the eye-opening response, the verbal 
response and the motor response. The motor response is assessed in the left and the right 
arm. If the scores in each arm are not the same, then the best score out of the two scores is 
used to determine the total GCS score. The total GCS score is the sum of the eye-opening 
response, the verbal response, and the best motor response. 


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Table 3 
Glasgow Coma Scale 
TEST 
RESPONSES 
VALUE 
Eye-opening 
No response 
1 
Response (1–4) 
To pain 
2 
To voice 
3 
Spontaneously 
4 
Verbal response (1–5) 
No response 
1 
 
Incomprehensible words 
2 
Inappropriate words 
3 
Disoriented 
4 
Oriented 
5 
Motor response (1–6) 
No response 
1 
Left arm 
Abnormal extension (decerebrate) 
2 
Right arm 
Abnormal flexion (decorticate) 
3 
Withdrawal 
4 
 
Localizes 
5 
 
Follows commands 
6 
 
The assessment is made at hospital admission, post-aneurysm-securing procedure, and 
pre-randomization for the determination of the GCS scores and the WFNS grades.  
Details of the three GCS components (eye opening, verbal, motor) will be recorded in the 
source documentation but only the total GCS score will be entered into the eCRF.  
Intubated subjects 
Subjects who are endotracheally intubated will have their verbal score extrapolated from 
their eye-opening and best motor score according to the following table (applicable for 
GCS and mGCS): 


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Table 4 
Derivation of verbal score for intubated subjects 
 
Eye score (1–4) 
Best motor score (1–6) 
1 
2 
3 
4 
1 
1 
1 
1 
2 
2 
1 
2 
2 
2 
3 
2 
2 
3 
3 
4 
2 
3 
3 
4 
5 
3 
3 
4 
4 
6 
3 
4 
4 
5 
Derived verbal score = −0.3756 + Motor Score × (0.5713) + Eye-opening Score × (0.4233) [Meredith 1998, 
Rutledge 1996]. 
Sedated/paralyzed subjects 
Subjects who are sedated or pharmacologically paralyzed should have their 
sedation/paralysis interrupted/reversed for these assessments. Assessments that are 
unreliable due to the influence of sedation or for other reasons are not to be recorded 
or used to determine subject eligibility for the study. Subjects who are still under the 
influence of pharmacological sedation at the time of randomization or who are, for 
whatever reason, not evaluable for baseline and regular daily neurological assessments are 
excluded from the study. 
Aphasic subjects 
The verbal score for aphasic subjects will depend on the severity of the aphasia and what 
verbal response the subject is actually able to produce. If the subject cannot produce speech 
at all, then the verbal score is 1, for no response. If the subject can speak but is replacing 
the expected words with inappropriate ones, then a score of 3, for inappropriate words, may 
be considered. If the subject does not respond to simple verbal commands, then pantomime 
or gestures with the body may be required. 


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7.2.2.1.2 World Federation of Neurological Societies grade 
The WFNS grade is a clinical measure of disease severity and is determined from the GCS 
score and an assessment of motor deficit as follows: 
Table 5 
WFNS grade 
WFNS grade 
GCS score 
Motor deficit* 
I 
15 
Present or Absent 
II 
14–13 
Absent 
III 
14–13 
Present 
IV 
12–7 
Present or Absent 
V 
6–3 
Present or Absent 
*Aphasia is considered equivalent to motor deficit. 
GCS = Glasgow Coma Scale; WFNS = World Federation of Neurological Societies. 
 
The GCS score is the sum of the eye-opening response, the verbal response, and the best 
motor response.  
The WFNS grade will be determined 3 times in un-sedated subjects at a) hospital 
admission, b) after recovery from the aneurysm-securing procedure (after external 
ventricular drainage for hydrocephalus, if required), and c) prior to randomization. The 
first assessment is used to document the baseline disease characteristics and the latter two 
are used for evaluation of subject eligibility into the study. 
The GCS scores, presence or absence of a motor deficit, and WFNS grades at admission, 
post aneurysm-securing procedure, and prior to randomization will be recorded in the 
source documentation and in the eCRF. 
7.2.2.1.3 Modified Glasgow Coma Scale 
The mGCS is used in conjunction with the aNIHSS [see Section 7.2.2.1.4] to detect 
episodes of clinical deterioration due to DCI.  
It is performed the same way as the GCS [see Section 7.2.2.1.1]. However, the total score 
is calculated as the sum of the eye-opening response, the verbal response, and the worst 
motor response out of the two arms tested. The worst motor response is used to enable the 
detection of any new focal deficits from one assessment to the next. The total mGCS score 
may range from 3 (worst) to 15 (best). 
The mGCS is performed as close as possible to the time of study drug initiation (within 
30 minutes prior to initiation), then every 6 hours (±1 h) while in the ICU (or equivalent) 
until Day 14 post-study drug initiation, for the determination of the mGCS score. The first 
mGCS assessment performed after the start of study drug may be performed earlier than 


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6 hours (±1 h) after the previous one, in order to ensure all subsequent assessments fall at 
a convenient time. If study drug is prematurely discontinued prior to Day 14 and the subject 
is still in the ICU (or equivalent), the mGCS will continue to be performed every 6 hours 
(±1 h) until Day 14. If the subject has been discharged to a regular ward, the mGCS is 
performed every 12 hours (±1 h) until Day 14. 
The mGCS is used to detect episodes of clinical deterioration due to DCI by comparison 
with the reference score (initially the one obtained within 30 minutes prior to study drug 
initiation. If a decrease of at least 2 points in the mGCS score occurs, the assessment must 
be repeated hourly (±15 min) for at least the first 2 hours. Thereafter, the reference score 
will depend on the clinical evolution of the subject. After sustained improvements or 
worsenings in clinical status, the new reference score will be recalibrated to reflect the best 
mGCS score attained by the subject immediately prior to an episode of clinical 
deterioration.  
The total mGCS scores and the individual components (eye opening, verbal, motor scores) 
are recorded in the source documentation. The total mGCS scores are collected in the 
eCRF. 
Sedated/paralyzed subjects 
Subjects who are sedated or pharmacologically paralyzed should have their 
sedation/paralysis interrupted/reversed for these assessments (at least once daily). 
However, if this is deemed unsafe for the subject, then these assessments can be waived 
for as long as the sedation/paralysis must continue. It is not recommended to administer 
long-acting sedative agents (e.g., fentanyl by continuous infusion, diazepam, barbiturates). 
The mGCS must not be performed in a subject who is still under the influence of 
sedation/paralysis. Assessments that are unreliable due to the influence of sedation or 
for other reasons are not to be recorded for study purposes, however the reason for 
the missing assessments must be documented in the medical chart. 
7.2.2.1.4 Abbreviated National Institutes of Health Stroke Scale 
The aNIHSS is used in conjunction with the mGCS to detect episodes of clinical 
deterioration due to DCI. 
It is a measure of limb movement and strength and is comprised of the motor section of the 
full NIHSS. Four separate scores from 0 (best) to 4 (worst) are determined for each limb 
(left arm, right arm, left leg, right leg). The total score is the sum of the individual scores 
corresponding to each limb: Total score = Left arm + Right arm + Left leg + Right leg. The 
total score may range from 0 (best) to 16 (worst). 
The aNIHSS is performed as close as possible to the time of study drug initiation (within 
30 minutes prior to initiation), then every 6 hours (±1 h) while in the ICU (or equivalent) 


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until Day 14 post-study drug initiation. If study drug is prematurely discontinued prior to 
Day 14 and the subject is still in the ICU (or equivalent), the aNIHSS will continue to be 
performed every 6 hours (±1 h) until Day 14. If the subject has been discharged to a regular 
ward, the aNIHSS is performed every 12 hours (±1 h) until Day 14.  
The aNIHSS is used to detect episodes of clinical deterioration due to DCI by comparison 
with the reference score (initially the one obtained within 30 minutes prior to study drug 
initiation). If an increase of at least 2 points in the aNIHSS score occurs, the assessment 
must be repeated hourly (±15 min) for at least the first 2 hours. Thereafter, the reference 
score will depend on the clinical evolution of the subject. After sustained improvements or 
worsenings in clinical status, the new reference score will be recalibrated to reflect the best 
aNIHSS score attained by the subject immediately prior to an episode of clinical 
deterioration.  
The total aNIHSS scores and the individual scores for each limb are recorded in the source 
documentation. The total aNIHSS scores are collected in the eCRF. 
Sedated/paralyzed subjects 
Subjects who are sedated or pharmacologically paralyzed should have their 
sedation/paralysis interrupted/reversed for these assessments (at least once daily). 
However, if this is deemed unsafe for the subject, then these assessments can be waived 
for as long as the sedation/paralysis must continue. It is not recommended to administer 
long-acting sedative agents (e.g., fentanyl by continuous infusion, diazepam, barbiturates). 
The aNIHSS must not be performed in a subject who is still under the influence of 
sedation/paralysis. Assessments that are unreliable due to the influence of sedation or 
for other reasons are not to be recorded for study purposes, however the reason for 
the missing assessments must be documented in the medical chart. 


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Table 6 
Abbreviated NIHSS 
Motor Arm and Leg: The limb is placed in the appropriate position: extend the arms (palms down) 90 
degrees (if sitting) or 45 degrees (if supine) and the leg 30 degrees (always tested supine). Drift is scored if 
the arm falls before 10 seconds or the leg before 5 seconds. The aphasic patient is encouraged using urgency 
in the voice and pantomime but not noxious stimulation. Each limb is tested in turn, beginning with the non-
paretic arm. Only in the case of amputation or joint fusion at the shoulder or hip may the score be ‘9’ and the 
examiner must clearly write the explanation for scoring as a ‘9’. 
 
0 = No drift, arm holds 90 (or 45) degrees for full 10 seconds.  
1 = Drift, arm holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other 
support. 
2 = Some effort against gravity, arm cannot get to or maintain (if placed in position) 90 (or 45) degrees, drifts 
down to bed, but has some effort against gravity. 
3 = No effort against gravity, arm falls. 
4 = No movement 
9 = Amputation, joint fusion explain: ______________________ 
Left Arm: ________ 
Right Arm: _________ 
 
 
0 = No drift, leg holds 30 degrees position for full 5 seconds. 
1 = Drift, leg falls by the end of the 5 second period but does not hit bed. 
2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. 
3 = No effort against gravity, leg falls to bed immediately. 
4 = No movement 
9 = Amputation, joint fusion explain:_________________ 
Left Leg: _________ 
Right Leg: _________ 
 
7.2.2.2 Primary endpoint assessments 
Clinical deterioration in the context of the primary efficacy endpoint of the study is defined 
in subjects in whom neurological scales are evaluable, as a worsening of at least 2 points 
compared to the reference score on the mGCS or the aNIHSS lasting for at least 2 hours. 
The subject meets the primary endpoint if the deterioration cannot be entirely attributed to 
causes other than cerebral vasospasm, as adjudicated by the CEC, based on review of 
clinical data provided by the investigator for the purpose of ruling out other causes. These 
data are described in Section 7.2.2.2.1.  
For any new neurological deterioration episode as defined above, occurring up to Day 14 
post-study drug initiation, the primary cause of the clinical deterioration and any potentially 
contributing causes (based on investigator local assessment) will be recorded in the eCRF. 
The results of examinations performed to diagnose the cause of the deterioration will also 
be recorded in the eCRF and a clinical narrative will be written as described below.  


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The above information will also be collected in the eCRF for subjects who experience an 
initial worsening of at least 2 points as described above, but are subsequently not evaluable 
for either the mGCS or the aNIHSS (e.g., due to continuous sedation), and therefore the 
duration of the worsening cannot be confirmed.  
Subjects who are not evaluable for neurological status at any time up to Day 14 post-study 
drug initiation, will be considered as meeting the primary efficacy endpoint if either rescue 
therapy was administered for a relevant vasospasm or the reason for not being evaluable is 
vasospasm-related, as confirmed by the CEC. Therefore, the results of any relevant exams 
performed which describe the subject’s condition during the period in which they were not 
evaluable, and a clinical narrative will also be collected in the eCRF.  
Exceptional circumstances may occur, resulting in a hospital discharge prior to Day 14 
post-study drug initiation and an incomplete set of neurological scale assessments. In this 
situation, a follow-up must be performed to collect relevant clinical information during the 
period between the discharge and Day 14, as described in Section 7.2.2.2.1. This follow-
up will be performed retrospectively for subjects who were enrolled under previous 
protocol versions and who were discharged prior to Day 14. 
If this follow-up reveals that the subject was re-hospitalized or transferred to another 
facility and DCI cannot be ruled out as a primary or contributing cause, the subject will be 
considered as meeting the primary endpoint. 
A clinical narrative is to be written in English by the investigator/delegate as soon as 
possible 
following 
Day 14 
post-study 
drug 
initiation. 
This 
narrative 
will 
describe/summarize the neurological deterioration episode including the nature and 
evolution of significant clinical findings, treatments initiated in response to the 
deterioration, and response to treatment. Results of specific tests (e.g., perfusion CT scan, 
MRI) may be summarized in the narratives. In addition to the above scenarios a subject 
narrative is also to be written if a subject becomes unevaluable at any time point for 
neurological scales or has at least one missing neurological assessment for other reasons. 
For subjects discharged earlier than 14 days post-study drug initiation, the outcome of the 
follow-up must be described in the narrative including all relevant clinical information that 
would allow the primary endpoint evaluation to be completed (i.e., to confirm or rule out 
the occurrence of clinical deterioration due to DCI up to Day 14 post-study drug initiation). 
Example narratives will be provided in the eCRF completion guideline to standardize the 
content of the narratives across the participating sites. 
7.2.2.2.1 Supportive data for primary endpoint evaluation 
Special assessments will be performed and recorded on the “Supportive data” eCRF pages 
if a subject experiences a worsening of at least 2 points on the mGCS or the aNIHSS within 
the 14 days following the initiation of study drug. These assessments are required by the 


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CEC to diagnose the primary and contributing causes of the deterioration and may vary 
according to the suspected diagnosis and the local routine work-up. However, a minimum 
set of assessments will be performed for all potential episodes of neurological deterioration, 
irrespective of the suspected underlying cause: 
• mGCS and aNIHSS assessments hourly for the following 2 hours after the initial 
neurological deterioration.  
• Blood sample for local laboratory analysis as close as possible to the time of the initial 
neurological deterioration, but no later than 1 hour after the confirmation of the 
deterioration, i.e., no later than 3 hours from the initial worsening. Serum sodium, 
creatinine, and the following arterial blood gases: SaO2, PaO2, PaCO2, and pH (if the 
subject is intubated/ventilated, along with the corresponding ventilator settings), or 
SpO2 (oxygen saturation in the blood as measured by pulse oximetry, for those not 
ventilated, along with the amount of any oxygen administrated) must be included as a 
minimum. The other laboratory parameters evaluated will be based on investigator 
judgment according to the specific clinical situation. If the repeated hourly neurological 
scales assessments cannot be completed because the subject becomes unevaluable the 
local laboratory tests are still to be performed.  
For confirmed episodes of neurological deterioration or when there is an initial worsening 
of at least 2 points, the duration of which cannot be confirmed because the subject becomes 
unevaluable due to a suspected central nervous system (CNS) cause, the following 
assessments (in addition to those listed above) are considered to be the minimum:  
• Cerebral CT scan within 6 hours of the initial neurological deterioration. 
• Cerebral angiogram (DSA or CTA) within 6 hours* of the initial neurological 
deterioration. 
*For subjects randomized into the study in the early treatment group, this angiogram may be waived if the 
pre-randomization angiogram was performed within 24 h of the initial neurological deterioration. 
Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
 
• Blood sample for serum S100b protein concentration (central assessment) drawn within 
1 hour of the confirmation of the neurological deterioration episode or within 3 hours 
from the initial worsening. 
Imaging performed as part of the routine work-up is to be centrally provided to support the 
CEC in their evaluation in the following situations: 
• if a subject becomes unevaluable for neurological status and rescue therapy is 
concurrently administered,  


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• if the reason for not being evaluable is vasospasm related. 
If images had already been submitted for a preceding episode with the same underlying 
cause, then additional images are not required. 
For all episodes of neurological deterioration and periods when a subject is not evaluable 
for neurological scales, depending on the clinical presentation of the subject and 
irrespective of the suspected underlying cause, additional assessments may include (but are 
not limited to):  
• Other laboratory parameters (e.g., electrolytes, biochemistry, hematology, coagulation, 
liver function tests, arterial blood gases, urinary density), analyzed locally. 
• Specific examinations (e.g., cerebral CT scan, cerebral angiogram, cerebral perfusion 
CT scan, EEG, ECG, chest X-ray, chest CT, pulmonary angiogram, TCD, MRI). 
• Vital signs (including ICP). 
• A hospital discharge summary or autopsy report as applicable, may also be submitted 
if it is believed to bring additional useful information to the CEC. 
For the exceptional cases when subjects are discharged earlier than 14 days post-study drug 
initiation, a follow-up must be performed on Day 14 post-study drug initiation, or as soon 
as possible after Day 14 and documented in the source notes. The follow-up is not required 
if the subject was discharged on Day 13 and there is at least one set of neurological scales 
assessment available on this day. The information may be collected from the patient or a 
proxy during a routinely performed or dedicated follow-up visit / telephone call or obtained 
from another healthcare facility. This follow-up will also be performed retrospectively for 
subjects who were enrolled under previous protocol versions and who were discharged 
prior to Day 14. 
The outcome of the follow-up must be described in the clinical narrative in the eCRF 
including all relevant clinical information that would allow the primary endpoint evaluation 
to be completed (i.e., to confirm or rule out the occurrence of clinical deterioration due to 
DCI up to Day 14 post-study drug initiation). If a new neurological deterioration event 
occurred, the appropriate eCRF pages are to be completed. The follow-up information must 
cover the period from hospital discharge to Day 14 post-study drug initiation and must 
include, but is not limited to: 
• Whether or not the subject was re-hospitalized or transferred to another facility during 
the above period, the corresponding date and reason for re‑hospitalization/transfer, and 
any relevant subsequent diagnosis made. 
• Clinical data describing the presence/absence of symptoms suggestive of clinical 
deterioration due to DCI, e.g., new focal neurological signs, deterioration in level of 


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consciousness, stroke and results from any supportive assessments performed 
(including brain imaging). 
• If a new cerebral CT scan was performed at the study site or another hospital (ideally 
up to Day 16 post-study drug initiation + 7 days), this scan may be used to 
replace/support a CT scan performed at hospital discharge (or earlier) and submitted to 
the imaging CRO.  
The results of the above additional assessments and the follow-up will be added to / entered 
in the source documentation and in the eCRF, described in the clinical narrative (as 
appropriate) and provided to the CEC to perform adjudication. In certain cases, the CEC 
may request additional clinical information, on top of that which was initially submitted, 
to ensure sufficient data is available to support their review. 
7.2.2.3 Cerebral angiograms 
All angiograms described in this section will be performed locally, shipped to the central 
imaging CRO (unless otherwise stated), and reviewed by independent expert readers. All 
images must be performed according to the Image Acquisition Guidelines (IAG; provided 
separately), and ideally on the same imaging equipment throughout the entire study. Details 
regarding the minimum technical requirements for validation of imaging equipment for 
study purposes are also contained in the IAG. Prior to enrolling subjects into the study, the 
imaging CRO will verify the ability of each participating site to comply with minimum 
technical and quality requirements for the cerebral angiograms via the submission of a test 
image (see IAG). 
DSA and CTA are both acceptable imaging modalities for the study. Magnetic resonance 
angiography is not an acceptable modality for this study. The choice between DSA and 
CTA is based on local routine standard of care post-aSAH and both modalities may be used 
throughout the study.  
A copy of all imaging (raw and DICOM) must be archived at the site for at least 25 years 
after study end unless agreed differently within the study agreement with Idorsia.  
The site must always keep the original image (unblinded with study subject details 
included) at the site in order to be able to confirm during audit or inspection that the blinded 
study images correspond to the correct study subjects. 
At study end, the imaging CRO will return copies of images which have been used in the 
study for IRC and CEC evaluation to each site. These images will not contain any 
confidential patient health identifiers, only the study‑subject number. 
A cerebral angiogram is performed at the following time points: 


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7.2.2.3.1 Hospital admission 
An angiogram is performed at hospital admission to document the aneurysmal cause of the 
SAH and the fulfillment of other angiogram-related entry criteria. If this angiogram was 
performed at a referral hospital, is of acceptable quality, and is available in digital format 
at the investigational site at the time of screening, it does not need to be repeated. However, 
if the angiogram was repeated at the investigational site, the second angiogram will be used 
for verification of the eligibility criteria and submitted to the imaging CRO. 
7.2.2.3.2 Post aneurysm-securing procedure 
For subjects who had their aneurysm repaired by endovascular coiling, an angiogram will 
be performed intra- or post-procedure according to local standard of care, to document the 
outcome of the aneurysm repair. This angiogram will be used to verify the study eligibility 
criteria, but will not be submitted to the imaging CRO. 
For subjects who had their aneurysm repaired by surgical clipping, a post-procedure 
angiogram may not always be routinely performed and therefore the outcome of the 
aneurysm repair may be confirmed by angiogram or by other means and documented in 
the subject’s medical chart. 
7.2.2.3.3 Prior to randomization 
An angiogram will be performed prior to randomization for those subjects enrolled in the 
early treatment* population, to document the presence of moderate to severe cerebral 
vasospasm at the time of randomization. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
7.2.2.3.4 At each episode of neurological deterioration (suspected CNS cause) 
An angiogram will be performed at each episode of neurological deterioration suspected 
to be due to a CNS cause, within 6 hours* of the start of the initial deterioration. An 
angiogram will also be performed when there is an initial worsening of at least 2 points the 
duration of which cannot be confirmed because the subject subsequently becomes 
unevaluable. If more than one angiogram was performed for the same episode of 
neurological deterioration (e.g., after the 6-hour time window), the investigator must 
submit all relevant angiograms to the imaging CRO, based on his/her clinical judgment. 
Routinely performed angiograms, if any, documenting the underlying cause are to be 
submitted if: 
• the subject becomes unevaluable on the neurological scales concurrently with rescue 
therapy administration or  
• the reason for not being evaluable is vasospasm related. 


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*For subjects randomized into the study in the early treatment group, this angiogram may be waived if the 
pre-randomization angiogram was performed within 24 h of the initial neurological deterioration. 
Recruitment into the early treatment group was discontinued from protocol version 6 onwards. 
 
7.2.2.4 Cerebral CT scans 
All CT scans described in this section will be performed locally, shipped to the central 
imaging CRO (unless otherwise stated), and reviewed by independent expert readers. All 
images must be performed according to the IAG (provided separately), and ideally on the 
same imaging equipment throughout the entire study. Details regarding the minimum 
technical requirements for validation of imaging equipment for study purposes are also 
contained in the IAG. Prior to enrolling subjects into the study, the imaging CRO will 
verify the ability of each participating site to comply with minimum technical and quality 
requirements for the CT scans via the submission of a test image (see IAG).  
Perfusion CT imaging is not an acceptable modality for this study and cannot be used to 
replace a conventional CT scan. However, if performed to evaluate an episode of 
neurological deterioration, a description of the results may be submitted to the CEC (e.g., in 
the clinical narrative [see Section 7.2.2.1]) as complementary information. 
A copy of all imaging (raw and DICOM) must be archived at the site for at least 25 years 
after study end unless agreed differently within the study agreement with Idorsia.  
The site must always keep the original image (unblinded with study subject details 
included) at the site in order to be able to confirm during audit or inspection that the blinded 
study images correspond to the correct study subjects. 
At study end, the imaging CRO will return copies of images which have been used in the 
study for IRC and CEC evaluation to each site. These images will not contain any 
confidential patient health identifiers, only the study‑subject number. 
A cerebral CT scan is performed at the following time points: 
7.2.2.4.1 Hospital admission 
A CT scan is performed at hospital admission to document the SAH, the baseline disease 
characteristics including clot size and the presence of IVH, and the fulfillment of other CT 
scan-related entry criteria. If this CT scan was performed at a referral hospital, is of 
acceptable quality, and is available in digital format at the investigational site at the time 
of screening, it does not need to be repeated. However, if the CT scan was repeated at the 
investigational site, the second scan will be used for verification of the eligibility criteria 
and submitted to the imaging CRO. 


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7.2.2.4.2 Post aneurysm-securing procedure 
A CT scan is performed at least 8 hours post procedure and within 24 hours prior to 
randomization to verify the study eligibility criteria.  
Any other routinely performed cerebral CT scan performed post aneurysm-securing 
procedure and prior to the above CT scan, if believed to be relevant by the investigator, 
will be submitted to the imaging CRO to aid in the detection of new or worsened infarcts 
and post-procedure complications/re-bleeding. 
7.2.2.4.3 At each episode of neurological deterioration (suspected CNS cause) 
A CT scan will be performed at each episode of neurological deterioration suspected to be 
due to a CNS cause, within 6 hours of the start of the initial deterioration 
[see Section 7.2.2.2.1]. A CT scan will also be performed if there is an initial worsening of 
at least 2 points for which the duration cannot be confirmed because the subject 
subsequently becomes unevaluable. If more than one CT scan was performed for the same 
episode of neurological deterioration (e.g., after the 6-hour time window), the investigator 
must submit all relevant CT scans to the imaging CRO, based on his/her clinical judgment. 
Routinely performed CT scans, if any, documenting the underlying cause are to be 
submitted if: 
• the subject becomes unevaluable on the neurological scales concurrently with rescue 
therapy administration or  
• the reason for not being evaluable is vasospasm related. 
7.2.2.4.4 Day 16 post-study drug initiation 
A CT scan will be performed where possible, on Day 16 post-study drug initiation for 
determination of the main secondary efficacy endpoint. If the CT scan cannot be performed 
on Day 16, then it is acceptable if the CT scan is performed up to 7 days after Day 16. Only 
if the subject is discharged from the hospital prior to Day 16, may this CT scan be 
performed on the day of hospital discharge. If no CT scan was performed on the day of 
hospital discharge, then the latest CT scan performed prior to discharge will be submitted 
to the imaging CRO. The subject must not be discharged prior to Day 14 [see 
Section 7.1.4].  
Depending on the specific situation, a CT scan performed later than Day 16 (+7 days) or 
prior to hospital discharge may be considered acceptable to replace a missing Day 16 scan 
or to support a scan performed too early. However, the acceptability of these scans will 
need to be assessed on an individual basis and discussed with the sponsor. 
If the subject is re-hospitalized/ transferred to another hospital after an early hospital 
discharge, and a new cerebral CT scan is performed (ideally up to Day 16 post-study drug 


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initiation + 7 days), this scan may be used to replace/support the earlier CT scan and 
submitted to the imaging CRO. 
7.2.2.5 Combined Glasgow Outcome Scale Extended / modified Rankin Scale 
interview 
The combined GOSE/mRS interview is designed to measure functional outcome and 
dependency at Week 12 post-aSAH, and is described in detail in Appendix 4. It is 
conducted as a face-to-face interview by a trained assessor at the Week 12 visit, allowing 
both the GOSE and mRS scores to be derived from the same interview. Depending on the 
clinical status of the subject, the interview may be performed with the subject and/or a 
proxy. If it is impossible for a subject who is already discharged to return to the 
investigational site for this visit (e.g., due to poor clinical status, distance from hospital), 
all attempts will be made to conduct the interview by telephone. 
The GOSE scores range from 1 (dead) to 8 (upper good recovery) and the mRS scores 
range from 0 (no symptoms) to 6 (dead) and are calculated by the interviewer based on the 
algorithm in Appendix 4. 
The results of the interview are recorded in the source documents and entered into the 
eCRF. 
Prior to conducting the first interview for the study, the assessor will successfully complete 
specific training. Further administration instructions can be found in the guidelines for the 
GOSE and mRS interview (provided separately). 
7.2.2.6 Montreal Cognitive Assessment 
The MoCA is a brief screening assessment for detecting cognitive impairment [see 
Appendix 5]. The scores range from 0 (worst) to 30 (best). The number of years of 
education is also collected since the total score may require adjusting based on this 
information. 
It is planned to be conducted face-to-face by a trained assessor up to 3 times during the 
study; after the aneurysm-securing procedure and prior to study drug initiation, at Day 14 
post-study drug start, and at the Week 12 visit. Since the ability to perform this assessment 
depends on the subject’s level of consciousness at the given time points, the MoCA will 
only be assessed in subjects with a GCS score ≥ 13 (based on routine local assessment) 
who are extubated (if applicable). The reason for not performing any MoCA will be 
collected in the source documentation and in the eCRF. 
Given the short time interval between the 3 assessments, parallel versions of the MoCA 
will be used at each of the time points to avoid any learning curve effect that could 
potentially bias the results. Each version will be identified as version 1, 2 or 3. Each 


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participating center will have a customized schedule which defines which of the 3 versions 
should be administered at each time point.  
The first MoCA will be performed after the aneurysm-securing procedure and prior to 
study drug initiation, as soon as the subject has fully recovered from the procedure 
(including recovery from sedation and anesthesia, with pain adequately controlled), has 
been extubated if applicable, has cerebrospinal fluid diversion in place (if required), and 
has provided informed consent to participate in the study. This MoCA can therefore be 
performed prior to randomization into the study.  
The second MoCA will be performed on Day 14 (±1 day) post-study drug initiation. If the 
subject requires hospital discharge prior to Day 14, the MoCA is performed on the day of 
discharge. 
The third MoCA will be performed at Week 12 (84 days ±7 days) post-aSAH. If it is 
impossible for a subject who is already discharged to return to the investigational site for 
the Week 12 visit (e.g., due to poor clinical status, distance from hospital), the MoCA is 
not performed and the reason for not performing the assessment is recorded in the source 
documentation and the eCRF. 
The results from each MoCA will be filed in the source documents and the scores for each 
section of the assessment will be entered into the eCRF. 
7.2.3 Safety assessments 
The definitions, reporting and follow-up of AEs/SAEs and pregnancies are described in 
Section 9. 
7.2.3.1 Weight and height 
Body weight and height will be measured during screening and recorded in the eCRF. 
7.2.3.2 Vital signs 
SBP will be measured in a supine or sitting position shortly before randomization and 
recorded in the source documentation. This measurement may be made by arterial line or 
by sphygmomanometer and will be used to confirm the absence of hypotension as defined 
in the exclusion criterion.  
SBP, diastolic BP (DBP), and HR will be measured via arterial line or sphygmomanometer 
in a supine or sitting position within 60 minutes prior to the start of the study drug infusion. 
These measurements will be used as the baseline values to which the values post-study 
drug initiation will be compared and will be entered into the eCRF. Prior to the initiation 
of study drug, BP must be controlled as per the Patient Management Guidelines [see 
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SBP, DBP, and HR will be measured every 6 hours (±1 h) in the ICU (or equivalent) during 
study drug administration and the results entered into the eCRF. After permanent study 
drug discontinuation, these assessments will continue to be performed every 6 hours (±1 h) 
until Day 14 post-study drug initiation. If the subject is no longer in the ICU (or equivalent), 
these assessments are performed every 12 hours (±1 h) until Day 14 post-study drug 
initiation. 
It is recommended to use the same position (supine or sitting) and the same method of 
measurement (arterial line or sphygmomanometer) throughout the study for an individual 
subject. 
7.2.3.3 Intracranial pressure 
ICP will be measured in subjects with ICP monitoring, before randomization to confirm 
the absence of high sustained ICP as defined in the exclusion criterion. The measurement 
will be recorded in the source documentation. 
ICP is subsequently measured at approximately the same time as the vital signs, within 
60 minutes prior to the start of study drug, then every 6 hours (±1 h) until Day 14 post‑study 
drug initiation, for as long as the ICP monitor is in place. 
These measurements are entered into the eCRF. It is recommended that where possible, the 
same method of ICP monitoring be used throughout the study for an individual subject. 
7.2.3.4 Central venous pressure 
Central venous pressure (CVP) will also be measured and recorded at the same time as 
ICP, if this monitoring is present. CVP is measured at end expiration without ventilation 
with the zero reference point (BP transducer) at the level of the left atrium. 
7.2.3.5 Body temperature 
Body temperature will be measured within 60 minutes prior to the start of study drug, then 
every 12 hours (± 1 h) until Day 14 post-study drug initiation. These measurements are 
entered into the eCRF.  
It is recommended that where possible, the same method of body temperature monitoring 
be used throughout the study for an individual subject. 
7.2.3.6 24-hour fluid intake and balance 
For subjects with a urine catheter, 24-hour fluid balance will be measured and recorded in 
the eCRF for as long as the catheter is in place, starting from the day of study drug initiation 
and ending on the day of permanent study drug discontinuation. On the day of study drug 
initiation, the first 24-hour period of measurement will include the time of study drug start, 
unless the available measurement is not representative of a full 24-hour period. In the latter 
case, the partial 24-hour measurement is not recorded, and the first measurement recorded 


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in the eCRF will start after the time of study drug initiation. On the day of permanent study 
drug discontinuation, the last 24-hour period recorded will include the time of study drug 
discontinuation.  
For subjects without a urine catheter, 24-hour fluid intake (including the volume of i.v. 
drugs and oral liquids administered) will be recorded, according to the periods described 
above. 
The start and end of a 24-hour period is based on local standard of care and does not 
necessarily correspond to measurements made from midnight to midnight. 
7.2.3.7 Electrocardiogram parameters 
A 12-lead ECG will be performed within 60 minutes prior to the start of study drug, and 
again at EOT, within 2 hours following permanent study drug discontinuation.  
For subjects that experience an AE related to a cardiac rhythm abnormality, an additional 
ECG will be performed as soon as possible to allow for further investigation of cardiac 
rhythm and repolarization characteristics. 
The following ECG parameters will be assessed and recorded in the eCRF at all time points, 
along with the date and time of the assessment: 
• RR, PR, QT, and QRS intervals 
• HR 
If the intervals cannot be measured reliably (e.g., subject is in atrial fibrillation), then the 
measurements are not recorded in the eCRF and the reason for the missing measurements 
is documented in the source documentation and the eCRF. 
7.2.4 Laboratory assessments 
7.2.4.1 Types of laboratory 
Both central and local laboratories will be used in this study. For the purpose of routine 
medical management of study subjects, the local laboratory results will be used. The results 
obtained from either the central or the local laboratory may be used by the investigator to 
report AEs. 
A central laboratory (see laboratory manual for contact details) will be used for all regularly 
scheduled protocol-mandated laboratory tests (with the exception of the screening 
assessments and the urine [and serum if applicable] pregnancy test at the Week 12 visit). 
Local laboratory results for all unscheduled tests performed in the work-up of neurological 
deterioration episodes will be collected and entered in the eCRF. All relevant local 
laboratory results will be recorded in the eCRF with the corresponding local normal ranges. 


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Local laboratory results of the regularly scheduled tests [parameters described in 
Section 7.2.4.2.1.2] will only be collected in exceptional circumstances (e.g., missing 
central laboratory results).  
Laboratory reports (except for S100b protein concentrations) will be provided by the 
central laboratory to the investigator/delegate. In the event of specific (pre-defined in the 
laboratory manual) laboratory abnormalities, the central laboratory will alert the sponsor 
and the site personnel.  
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, as per 
investigator judgment, 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 laboratory abnormalities 
as per investigator judgment detected after signing of the ICF and before randomization 
must be reported as an AE if they meet the criteria for an AE related to a study-mandated 
procedure [see Section 9.1.7], and must be followed until the value returns to within the 
normal range or is considered stable and no longer clinically relevant. Any clinically 
relevant laboratory abnormalities as per investigator judgment detected after 
randomization and until the end of the 24-hour safety follow-up period (i.e., up to 24 hours 
after study drug discontinuation), must be reported as an AE, and must be followed until 
the values return to within the normal range or are considered stable and no longer 
clinically relevant. If a clinically relevant laboratory abnormality is not observed on a 
central laboratory report, the local laboratory result may be requested by the sponsor for 
documentation purposes. If the abnormality has not yet returned to within normal ranges 
by the EOS visit, the sponsor may request the reporting of the latest local laboratory value 
obtained prior to / on the day of the EOS visit.  
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual (provided separately). 
7.2.4.2 Laboratory tests 
7.2.4.2.1 Blood tests 
7.2.4.2.1.1 Screening 
A blood sample will be drawn during the screening period for confirmation of the study 
entry criteria (i.e., serum total bilirubin, PaO2 in subjects who are intubated/ventilated, 
serum pregnancy test for women of childbearing potential). This sample will be analyzed 
by the local laboratory and the results recorded in the source documentation only. 


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7.2.4.2.1.2 Prior to study treatment start and during observation period for the primary 
endpoint 
Blood for hematology and biochemistry assessments will be drawn within 60 minutes prior 
to study drug infusion start (baseline assessment), then every second day thereafter until 
Day 14 post-study drug initiation. The first of the post-baseline samples will be drawn on 
the second day after the baseline assessment. A sample will be drawn within the 2 hours 
following permanent study drug discontinuation, if a regularly scheduled sample was not 
already drawn for analysis on that day. These samples are analyzed centrally.  
The laboratory parameters to be analyzed are the following: 
Hematology: 
• Hemoglobin (g/L) 
• Hematocrit (%) 
• Leukocyte count (with differential count*) (109/L) 
• Platelet count (109/L) 
*The differential leukocyte count is only reported to the site and the sponsor if the total leukocyte count 
is abnormal. 
Blood chemistry: 
• Sodium, potassium (mmol/L) 
• Creatinine (mol/L) 
• Blood urea nitrogen (mmol/L) 
• ALT (U/L), AST (U/L), alkaline phosphatase (U/L) 
• Total bilirubin* (mol/L) 
• Gamma glutamyl transferase (IU/L) 
• Albumin (g/L) 
• C-reactive protein (mg/L) 
Biomarker: 
• S100b protein (g/L) 
If a routine every other day S100b biomarker assessment falls on the same day as a 
neurological worsening episode of suspected CNS cause, and an S100b sample has already 
been drawn for the worsening episode, the regular S100b collection does not need to be 
repeated. 
* If total bilirubin is abnormal, the central laboratory will automatically analyze and report 
direct bilirubin. 


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7.2.4.2.1.3 Episodes of neurological deterioration 
A blood sample will be drawn and analyzed locally for each episode of confirmed 
neurological deterioration or when there is an initial neurological worsening the duration 
of which cannot be confirmed. 
The sample will be drawn as close as possible to the time of the initial neurological 
deterioration, but no later than 1 hour after the confirmation of the deterioration or within 
3 hours after the initial worsening. Serum sodium, creatinine, and the following arterial 
blood gases: SaO2, PaO2, PaCO2, and pH (if the subject is intubated/ventilated), must be 
included as a minimum.  
The other laboratory parameters evaluated will be based on investigator judgment 
according to the specific clinical situation. The results from these locally assessed 
laboratory samples will be entered into the eCRF. However, if the neurological 
deterioration episode is suspected to be due to an underlying CNS cause, then the 
laboratory assessments must include serum S100b protein concentration which will be sent 
to the central laboratory for analysis. 
Local laboratory test result should be entered in the eCRF if available from routine standard 
of care assessments when the subject becomes unevaluable without an initial neurological 
worsening. 
7.2.4.2.2 Urine tests 
A urine pregnancy test will be performed at the Week 12 visit for women of childbearing 
potential. If pregnancy is suspected at any time, a locally analyzed serum pregnancy test 
must be performed immediately. 
Reporting procedures of pregnancy are described in Section 9.4.1. 
7.2.5 Quality of Life assessments 
The QoL assessments are to be completed at the Week 12 visit, where possible, after the 
MoCA and the GOSE/mRS interview and in the following order: SS-QOL, Ox-PAQ, 
EQ-5D. Additionally, EQ-5D is to be collected at the EOS visit.  
7.2.5.1 Stroke Specific Quality of Life 
The SS-QOL is a patient-reported outcome measure developed to provide an assessment 
of health-related QoL specific to patients with stroke. It is comprised of 49 items that cover 
12 domains (energy, upper extremity function, work/productivity, mood, self-care, social 
roles, family roles, vision, language, thinking, and personality) and 13 questions comparing 
post-aSAH status with pre-aSAH status. It has been validated for use in patients with stroke 
(including aSAH) [Williams 1999, Boosman 2010].  


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Subjects are asked to complete the questionnaire at the Week 12 visit by responding to 
each of the first 49 questions using the appropriate response (modeled on a 5-point Likert 
scale) and a recall period of 1 week, and the 13 subsequent questions (with one of the 
4 potential responses provided). If the subject is unable to complete the questionnaire, a 
proxy (e.g., family member, caregiver, close friend) is asked to complete the questionnaire. 
The information on who completed the questionnaire (subject or proxy) will be collected. 
If the subject is unable to return to the investigational site for the Week 12 visit, all attempts 
are to be made to have the subject or proxy complete the questionnaire remotely and return 
it by post to the site. Depending on to local regulations, a study staff member from the 
investigative site may also conduct the Week 12 visit at the subject’s place of residence. It 
is estimated that 10–15 minutes are required to complete the questionnaire. 
The SS-QOL yields both domain scores and an overall SS-QOL summary score. The 
domain scores are unweighted averages of the associated items while the summary score 
is an unweighted average of all twelve domain scores [Williams 1999]. The completed 
questionnaire is filed in the source documents and the answers to the individual questions 
are entered into the eCRF. 
A sample of the SS-QOL (in English) is provided in Appendix 6.  
The sponsor has been granted a license agreement for the use of the SS-QOL questionnaire 
and for performing additional translations as needed. 
7.2.5.2 Oxford Participation and Activities Questionnaire 
The Ox-PAQ is a patient-reported generic health-related QoL instrument developed to 
assess participation, activities, and level of independence. The instrument assesses the 
ability of individuals to engage in activities (such as work, hobbies, daily routines) and the 
level of dependency an individual has on others. It is comprised of 23 questions that cover 
3 domains (routine activities, emotional well-being, and social engagement) [Morley 2013, 
Kelly 2015, Morley 2016]. 
At the Week 12 visit, subjects are asked to indicate for each question how often they had 
difficulties with the particular activity or feeling over the past week, using responses 
modeled on a 5-point Likert scale. If the subject is unable to complete the questionnaire it 
is not completed by a proxy. If the subject is unable to return to the investigational site for 
the Week 12 visit, all attempts are to be made to have the subject complete the 
questionnaire remotely and return it by post to the site. Depending on local regulations, a 
study staff member from the investigative site may also conduct the Week 12 visit at the 
subject’s place of residence. It is estimated that 8–10 minutes are required to complete the 
questionnaire. The completed questionnaire is filed in the source documents and the 
answers to the individual questions are entered into the eCRF. 


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The Ox-PAQ has not yet been validated in aSAH and testing will be conducted separately 
and in parallel to the REACT study. 
A sample of the Ox-PAQ (in English) is provided in Appendix 8.  
The sponsor has been granted a license agreement for the use of the Ox-PAQ and for 
performing additional translations as needed. 
7.2.5.3 EQ-5D 
The EQ-5D (5L version) is a patient-reported outcome measure developed to assess generic 
health-related QoL. It is comprised of 5 domains (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) and a visual analog scale (VAS) assessing overall 
health. 
For each of the domains, subjects are asked at the Week 12 visit to tick the box 
corresponding to the statement that best describes their health on the day of the assessment. 
The subject is also asked to mark an ‘X’ on the VAS to indicate how their overall health is 
on the day of the assessment. If the subject is unable to complete the questionnaire, a proxy 
(e.g., family member, caregiver, close friend) is asked to complete the questionnaire. The 
information on who completed the questionnaire (subject or proxy) will be collected. If the 
subject is unable to return to the investigational site for the Week 12 visit, all attempts are 
to be made to have the subject or proxy complete the questionnaire remotely and return it 
by post to the site. Depending on local regulations, a study staff member from the 
investigative site may also conduct the Week 12 visit at the subject’s place of residence. It 
is estimated that 5 minutes are required to complete the questionnaire. 
During the EOS visit at 24 weeks post-aSAH the subject will be contacted by telephone to 
complete the EQ-5D (5L) telephone interview version by the site. The self-complete paper 
version will be provided in advance to be used as a reference by the responder during the 
call. If the subject cannot be reached by telephone the self-complete paper version must be 
completed by the subject/proxy and returned by post to the site. 
The completed questionnaires are filed in the source documents and the answers to the 
individual questions are entered into the eCRF by the site. 
A 1-digit number results from the statement that is selected by the subject for each domain. 
The digits for the five domains can be combined into a 5-digit number that describes the 
subject’s health state. Further details on the instrument and its scoring, and a list of related 
publications can be found in the EQ-5D-5L user guide, available on the EuroQol website 
(www.euroqol.org). 
A sample of the EQ-5D (5L self-complete version, in English) is provided in Appendix 7.  


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The sponsor has been granted a license agreement for the use of the EQ-5D questionnaire 
and for performing additional translations as needed. 
7.2.6 Pharmaco-economic assessments 
In addition to the interventions described in Section 5.2.5, the following information will 
be collected from randomization until initial hospital discharge, and from initial hospital 
discharge until Week 12, for pharmaco-economic purposes: 
• Length of stay in the acute care setting including the ICU (or equivalent unit), a 
specialized care ward (e.g., neurosurgery, neurology), and a general care ward; 
• Length of stay in a rehabilitation unit/center and rehabilitation intensity; 
• Length of stay in a long-term care facility (e.g., medicalized facility, non-medicalized 
facility, nursing home, assisted living facility, other); 
• Duration of home care support (nurse and physiotherapy visits at home, requirement 
for a caregiver / healthcare worker at home); 
• Location to where the subject was discharged after the initial hospitalization at the 
investigational study center. 
If a subject is discharged from the investigational site prior to the Week 12 visit, he/she 
will be provided with forms to be completed by the relevant healthcare workers in order to 
collect the above information, as applicable, for the period from hospital discharge to 
Week 12. 
At EOS 24 weeks post-aSAH (168 days ± 14 days), the pre-aSAH employment/student 
status, the current employment/student status, and the date of return to work (or to an 
educational institution, for students, as applicable) will be collected by the study site staff 
from the subject (or proxy, as applicable) via telephone or postal questionnaire and 
captured in the clinical database. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol 
Subjects who complete the study up to and including the EOS visit are considered to have 
completed the study as per protocol. This includes subjects who prematurely discontinue 
study drug, provided the EOS visit has 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 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost to 


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follow-up. If a subject withdraws consent, no further data will be collected in the eCRF 
from the date of withdrawal onward. The investigator may withdraw a subject from the 
study (without regard to the subject’s consent) if he/she believes that continued 
participation in the study would be contrary to the best interests of the subject. Withdrawal 
from the study may also result from a decision by the sponsor for any reason, including 
premature termination or suspension of the study. 
Subjects are considered as lost to follow-up if all repeated 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 potential methods of 
contact such as telephone number, home address, email address, person to be contacted if 
the subject cannot be reached). If the subject cannot be reached, the site must make 
reasonable repeated efforts 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 3 contacts (e.g., telephone calls, or e-mails) must 
be placed to the last available telephone number or email address) and 1 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 withdrawal 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 best efforts to schedule a last appointment / telephone 
call to assess the safety and well-being of the subject. 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 the 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 who are still in 
the study and/or their proxies/legal representatives (as applicable), and ensure 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. Depending on the reason 
for premature study termination, the investigator may also inform subjects who are no 
longer in the study and/or their proxies / legal representatives (as applicable). 
In addition, if the investigator suspends or terminates the 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 the study, the 
investigator must promptly notify the sponsor personnel and provide a detailed written 
explanation of the termination or suspension. 
8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local regulations. Such care may include use of 
drugs which were forbidden during concomitant study treatment administration. 
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. 
AEs include: 
• Exacerbation of a pre-existing disease if considered medically relevant. 
• 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. 


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• Continuous persistent disease or symptoms present at study start that worsen following 
the signing of the ICF. 
• 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 as per investigator judgment, or led to interruption or permanent 
discontinuation of study treatment. 
For the purposes of this study, certain reported AEs are considered to be of specific interest 
and will be grouped together and displayed by broader categories (i.e., lung complications, 
hypotension, anemia, cerebral hemorrhage, cerebral edema, fluid retention, hepatic 
disorders, tachyarrhythmia). 
9.1.2 Definition of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least 1 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 
medically significant based upon appropriate medical judgment, as they may jeopardize 
the subject, and/or 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). 


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9.1.3 Definition of waived serious adverse events 
The decision to have waived SAEs in a study is appropriate when the safety and tolerability 
profile of the study drug has been well characterized, allowing a clear understanding of the 
difference between drug-related and disease-related AEs. In addition, SAEs can only be 
waived for double-blind studies when an IDMC exists that will ensure the monitoring of 
these SAEs during the study.  
The SAEs listed below are due to the underlying disease, and are therefore expected to 
occur in this patient population (e.g., cerebral vasospasm). In this study, they will be 
waived. This means that they will not require reporting to the sponsor’s Global Drug Safety 
department in an expedited way and on an SAE form, and that they will be reported only 
on the AE pages of the eCRF as serious. Therefore, they will be entered only into the 
clinical database and not into the drug safety database. 
The waived SAEs for this study are the following: 
• Any type of cerebral/brain infarction or ischemia (includes all specific sites within the 
brain), cerebral vascular accident, stroke. 
• Cerebral/brain hemorrhage or hematoma (includes all specific sites within the brain). 
• DIND, neurological deterioration, clinical deterioration due to DCI, delirium, 
confusion, disorientation, aphasia, paresis/paralysis (including hemiparesis, limb 
weakness, limb paralysis). 
• Ruptured cerebral aneurysm (re-bleeding of the original cerebral aneurysm). 
• Complications related to the initial aneurysm-securing procedure. 
• Cerebral vasospasm. 
• Brain edema. 
• Hydrocephalus. 
• Intracranial hypertension. 
9.1.4 Definition of suspected unexpected serious adverse reactions 
The expectedness of an SAE is determined by the sponsor according to the reference safety 
information (RSI) section provided in the most recent version of the IB.  
Any SAE that is assessed as related and unexpected against the RSI is known as a SUSAR 
(suspected unexpected serious adverse reaction). Waived SAEs [Section 9.1.3] are 
considered to be expected due to the underlying disease and are therefore not normally 
considered as a SUSAR. 
Any SUSAR must be reported by the sponsor/CRO to relevant health authorities, and 
investigators. Submission to central/local IECs/IRBs will be done as per their requirements. 


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9.1.5 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. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.1.2]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations see Section 9.3.2. 
9.1.6 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. 
9.1.7 Relationship to protocol-mandated procedure 
An AE/SAE is defined as related to 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. 
The determination of the likelihood that a protocol-mandated procedure caused the 
AE/SAE will be provided by the investigator. 
9.2 Time period and frequency for adverse event / serious adverse event 
assessment and follow-up 
The occurrence of an AE/SAE may come to the attention of study personnel during study 
visits, telephone calls or interviews of study participants presenting for medical care.  


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At the Week 12 and at the EOS visit, the investigator will inquire about the occurrence of 
AE/SAEs since hospital discharge and since the Week 12 visit, respectively or since the 
last contact with the subject. 
9.2.1 Follow-up of adverse events 
AEs still ongoing at the EOS visit must be followed up until resolution, until 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, 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 and time from study drug initiation up to 24 hours after study 
treatment discontinuation (i.e., the 24-hour safety follow-up period) must be recorded on 
AE forms of the eCRF. Those AEs occurring from signature of the ICF until EOS will also 
be recorded on an AE form in the eCRF, if they are believed to be related to a protocol-
mandated procedure [see Section 9.1.7]. 
Information to be collected in an AE form in the eCRF includes date and time of onset, 
action taken with the study treatment, outcome of AE, date of resolution (if applicable) and 
principal investigator’s (PI’s) assessment of seriousness and intensity, and relationship to 
study treatment, study design or protocol-mandated procedures. For AEs related to cardiac 
rhythm abnormalities, additional ECG parameters may be collected [see Section 7.2.3.7]. 
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity should be reported on the AE form. If the AE lessens in intensity, no change in 
the severity is required to be reported. 
For AEs ongoing at the start of study treatment, worsening of the AE after the start of study 
treatment will be recorded as a separate AE with the new intensity.  
Follow-up information on any ongoing AEs obtained after the subject’s EOS visit will not 
be collected in the eCRF. 
9.3.1.1 Reporting of acute respiratory distress syndrome 
To standardize the reporting of acute respiratory distress syndrome (ARDS), it is 
recommended to consider the following definitions [ARDS Definition Taskforce 2012]. 
• Mild ARDS: 300 ≥ PaO2/FiO2 > 200 with Positive End Expiratory Pressure (PEEP) or 
Continuous Positive Airway Pressure (CPAP) > 5 cm H2O  


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• Moderate ARDS: 200 ≥ PaO2/FiO2 > 100 with PEEP > 5 cm H2O  
• Severe ARDS: 100 ≥ PaO2/FiO2 with PEEP > 5 cm H2O  
In addition, the following criteria should be met:  
• Acute onset (within 1 week of known clinical insult). 
• Bilateral opacities on chest X-ray (not explained by effusions, collapse, or nodules).  
• Respiratory failure not fully explained by heart failure or fluid overload (objective 
assessment such as echocardiogram recommended if no risk factor). 
9.3.2 Additional reporting procedure for serious adverse events 
All SAEs (except those that are waived) with an onset date and time from study drug 
initiation up to EOS must be recorded on an SAE form, regardless of the 
investigator-attributed causal relationship with study treatment or study-mandated 
procedures. Those SAEs occurring from signature of the ICF until EOS will also be 
recorded on an SAE form, if they are believed to be related to a protocol-mandated 
procedure [see Section 9.1.7]. 
These SAEs must be reported by the investigator to the sponsor’s Global Drug Safety 
department (see contact details on the SAE form) within 24 hours of the investigator’s first 
knowledge of the event. The investigator must complete the SAE form in English and must 
assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
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 or has already 
been discharged home, it is the investigator’s responsibility to contact the hospital or the 
subject to obtain all SAE-relevant information and documentation. 
New SAEs occurring after the EOS visit 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. 


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9.4 Pregnancy 
If despite the negative serum pregnancy test at screening a woman becomes pregnant while 
on study treatment, study treatment must be permanently discontinued [see 
Section 5.1.3.4.1]. 
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 the Week 
12 visit 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). Pregnancies are not considered to be an AE and therefore are not recorded as such 
in the eCRF. 
The investigator must complete the pregnancy form in English. 
9.4.2 Follow-up of pregnancy 
Any pregnancies as described in Section 9.4.1 must be followed up to their conclusion and 
the outcome must be reported to the sponsor’s Global Drug Safety department. 
9.5 Breastfeeding women 
Women who were breastfeeding at the time of the aSAH must agree to refrain from 
breastfeeding for the duration of the treatment and until 30 days after the discontinuation 
of study drug. It is unknown whether clazosentan may be excreted into breast milk. 
9.6 Reporting of study treatment overdose, misuse, abuse and medication 
errors 
Study treatment overdose (defined as higher than the dose of study treatment prescribed), 
and study treatment errors will be reported as an AE when associated with signs or 
symptoms. 
In addition, study treatment errors must be documented in the study drug log of the eCRF. 
Misuse (e.g., medication error) and abuse of the study treatment will be reported as an 
AE/SAE. 


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9.7 Study safety monitoring 
Study safety information (AEs, SAEs, laboratory results, vital signs, and study-specific 
examinations as required) is monitored and reviewed on a continuous basis by the sponsor 
(who has the responsibility of ensuring subjects’ safety as well as data quality).  
The sponsor may request additional data pertaining to the diagnostic work-up of an AE or 
SAE (e.g., medical imaging, local laboratory values) for the purpose of monitoring safety. 
Such additional data may be shared with external experts. 
10 STATISTICAL METHODS 
10.1 Analysis sets 
10.1.1 Screened analysis set 
The Screened analysis set includes all subjects who have given informed consent to 
participate in the study and have a subject identification number. 
10.1.2 Randomized analysis set 
The Randomized analysis set includes all subjects who have been assigned to a study 
treatment. 
10.1.3 Full analysis set 
The Full analysis set (FAS) includes all subjects from the Randomized analysis set who 
have started the study treatment. The rationale for this choice of the FAS is that, per study 
design, due to the emergency setting, the investigator has the possibility to withdraw 
randomized subjects from the study before study drug initiation for safety or other reasons 
(e.g., due to a sudden deterioration of the clinical status post-randomization). Defining the 
FAS as all subjects who have started study treatment is expected to preserve the 
intent-to-treat principle, because: a) randomized but untreated subjects will be rare (in 
previous Phase 3 studies, i.e., CONSCIOUS-2 and -3, less than 1% of the randomized 
subjects were not treated), and b) the decision whether or not to begin treatment cannot be 
influenced by knowledge of the assigned treatment.  
Nevertheless, the reasons for not treating these subjects and the potential bias arising from 
this specific exclusion will be carefully examined.  
To adhere to the intent-to-treat principle as much as possible, subjects will be evaluated 
according to their assigned study treatment (not actual treatment received) and stratum 
information as recorded in the IRT system.  
Unless otherwise stated, all available efficacy data for the primary and secondary endpoints 
will be included in the analyses up to the planned analysis time point, regardless of study 
treatment discontinuation and/or use of rescue therapies. 


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10.1.4 Per-protocol analysis set 
The Per-protocol analysis set (PPS) comprises all subjects from the FAS who complied 
with the protocol sufficiently to be likely to exhibit the treatment effects. 
Criteria for sufficient compliance include adequate exposure to treatment, availability of 
key endpoint measurements and absence of major protocol deviations that have an impact 
on the treatment effect assessment for the primary endpoint.  
The precise reasons for excluding subjects from the PPS will be detailed in the statistical 
analysis plan (SAP) before making the full randomization information available. 
10.1.5 Safety analysis set 
The Safety analysis set includes all subjects who started study drug (as recorded in the 
eCRF).  
Subjects will be evaluated according to the actual treatment they received, which may 
differ from the randomly assigned treatment. 
10.1.6 Other analysis sets 
Other analysis datasets will be defined in the SAP (or corresponding SAPs), e.g., QoL, 
pharmaco-economics and subgroups of interest. 
10.1.7 Usage of the analysis sets 
Table 7 describes the analysis sets used for the analysis of each data set. 
Subject listings will be produced on the Screened analysis set, unless otherwise specified. 


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Table 7 
Analysis datasets usage 
 
Analysis sets 
Analyses 
SCR 
RND 
FAS 
PPS 
SAF  
Subject disposition 
X 
 
 
 
 
Protocol deviations, Analysis sets 
 
[X] 
X 
(x) 
 
Demographics characteristics 
 
[X] 
X 
(x) 
 
Baseline disease characteristics 
 
[X] 
X 
(x) 
 
Medical history and current medical conditions 
 
[X] 
X 
(x) 
 
Previous and concomitant therapies 
 
[X] 
X 
(x) 
 
Study treatment exposure 
 
 
 
(x) 
X 
Primary efficacy endpoint 
 
(x) 
X 
(x) 
 
Secondary efficacy endpoints 
 
(x) 
X 
(x) 
 
Exploratory efficacy endpoints 
 
 
X 
 
 
Quality of Life endpoints 
 
 
X 
 
 
Pharmaco-economic endpoints 
 
 
X 
 
 
Safety endpoints 
 
 
 
 
X 
Note: X: main analysis, [X]: if RND and FAS differ by more than 5%, some tables may be replicated on the RND; (x): 
Sensitivity analysis to be conducted only if > 5% difference of set size with set used for main analysis.  
FAS = Full analysis set; PPS = Per-protocol analysis set, RND = Randomized analysis set; SAF = Safety analysis set; 
SCR = Screened analysis set 
10.2 Variables 
In this section, variables are defined in detail for the primary and secondary efficacy 
endpoints and for the safety endpoints. Variables for all other endpoints will be defined in 
detail in the SAP. 
10.2.1 Primary efficacy variable 
The primary endpoint is the occurrence of clinical deterioration due to DCI from study 
drug initiation up to 14 days post-study drug initiation [see Section 6.1.1]. 
According to the rules specified in the CEC charter, the CEC will define the occurrence as 
a binary variable (yes/ no) for each subject submitted. 
It is assumed that the death status (within 14 days post-study drug initiation) and the 
primary endpoint assessment from the CEC will be available at the time of the final 
analysis. 
10.2.2 Secondary efficacy variables 
10.2.2.1 Main secondary variable 
The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at 
Day 16 post-study drug initiation defined as:  


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• all- cerebral infarction ≥ 5 cm3 or 
• cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI [see 
Section 6.1.2.1]. 
According to the rules specified in the CEC charter, the CEC will define the occurrence as 
a binary variable (yes/ no) for each subject. 
It is assumed that the assessment from the CEC is available at the time of the final analysis. 
10.2.2.2 Other secondary efficacy variable 
The other secondary endpoints are:  
• the long-term clinical outcome assessed by the mRS at Week 12 post-aSAH, 
dichotomized into poor outcome (score ≥ 3) and good outcome (score < 3) and  
• the long-term clinical outcome assessed by the GOSE at Week 12 post-aSAH, 
dichotomized into poor outcome (score ≤ 4) and good outcome (score > 4). 
The mRS scores range from 0 (no symptoms) to 6 (dead) and the GOSE scores range from 
1 (dead) to 8 (upper good recovery) and are calculated by the interviewer based on the 
algorithm in Appendix 4. 
The mRS will be dichotomized into poor (a score of 3 to 6) vs good (a score of 0 to 2) and 
the GOSE score into poor (a score of 1 to 4) vs good (a score of 5 to 8). 
10.2.3 Safety variables 
The variables described in this section are to be used for the derivation of the safety 
endpoints described in Section 6.2. 
10.2.3.1 Adverse events 
An AE is defined as any event that is recorded on the AE eCRF module with an onset 
date/time ≥ date/time of informed consent and ≤ EOS. 
TEAEs are those with an onset date/time ≥ start date/time of study treatment up to 24 hours 
after study treatment discontinuation. For SAEs, this period is extended to EOS. 
The handling of missing or incomplete date/time of AEs will be described in the SAP. 
10.2.3.2 Laboratory data 
Laboratory analyses are based on both central and local laboratories [see Section 7.2.4].  
For regularly scheduled protocol-mandated laboratory tests, the results obtained from the 
central laboratory will be considered first.  


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Baseline laboratory test refers to the latest laboratory test performed prior to the start of 
study treatment.  
No imputation for missing laboratory values will be performed unless necessary, in which 
case this will be described in detail in the SAP. 
EOT laboratory test refers to the laboratory test performed at EOT. If no laboratory data 
are available at EOT, the results of the latest available post-baseline laboratory tests 
performed prior to EOT date/time are used for the analysis. 
For each continuous laboratory parameter, the following variables will be summarized:  
• Absolute value at each scheduled assessment,  
• Absolute change from baseline to each scheduled assessment,  
• Treatment-emergent marked laboratory abnormalities (i.e., from study drug initiation 
and up to 24 hours after EOT).  
For categorical laboratory parameters, the following variables will be summarized:  
• Proportion of subjects by categories at each time point.  
Treatment-emergent marked laboratory abnormalities are those which are not present at 
baseline (e.g., change from no marked abnormality to any marked abnormality) or if a 
worsening occurred, as compared to the corresponding value at baseline (e.g., change from 
a pre-existing abnormality at baseline to a worse category of abnormality). Abnormality 
thresholds for laboratory data will be defined in the SAP.  
For all unscheduled tests performed in the work-up of neurological deterioration episodes, 
results obtained from local laboratories, no normalization of result and references ranges 
will be performed unless necessary, in which case this will be described in detail in the 
SAP.  
Data listings with individual subject data will be provided for the Safety analysis set 
including all laboratory parameters assayed during the study, centrally and locally. 
10.3 Description of statistical analyses 
All available data for each subject will be used in all statistical analyses unless otherwise 
specified.  
Unless otherwise stated, all available efficacy data for the primary and secondary endpoints 
will be included in the analyses up to the planned analysis time point, regardless of study 
treatment discontinuation and/or use of rescue therapies. 


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All analyses will be presented by treatment arms, i.e., clazosentan 15 mg/h and placebo, 
and also, when relevant, by population group (early treatment* vs high-risk prevention). 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards 
10.3.1 Overall testing strategy 
Four null hypotheses will be tested according to a fixed-sequence procedure, at the 
two-sided significance level of 0.05 until first non-rejection.  
The first null hypothesis is that there is no difference between clazosentan 15 mg/h and 
placebo in the occurrence of clinical deterioration due to DCI from study drug initiation up 
to 14 days post-study drug initiation.  
The alternative hypothesis H1a is that there is a difference between these arms: 
H10: p11 = p10 
vs 
H1a: p11 ≠ p10 
Here p10 and p11 denote the incidence of clinical deterioration due to DCI in the placebo 
and clazosentan arms, respectively. This hypothesis will be tested at a two-sided 
significance level of 0.05. 
Superiority will be concluded if the upper limit of the two-sided 95% confidence interval 
(CI) for the relative risk of clazosentan compared to placebo is lower than 1.  
The second null hypothesis H20, which will be tested if H10 is rejected, assumes no 
difference between clazosentan and placebo in the occurrence of clinically relevant 
cerebral infarction at Day 16 post-study drug initiation defined as: all-cause cerebral 
infarction ≥ 5 cm3 or cerebral infarction < 5 cm3 in subjects with clinical deterioration due 
to DCI. The alternative hypothesis H2a is that there is a difference between these arms: 
H20: p21 = p20 
vs 
H2a: p21 ≠ p20 
Here p20 and p21 denote the incidence of occurrence of clinically relevant cerebral infarction 
at Day 16 post-study drug initiation defined as: all-cause cerebral infarction ≥ 5 cm3 or 
cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI in the placebo 
and clazosentan arms, respectively. This hypothesis will be tested at a two-sided 
significance level of 0.05. 
Superiority will be concluded if the upper limit of the two-sided 95% CI for the relative 
risk of clazosentan compared to placebo is lower than 1. 
The third null hypothesis H30, which will be tested if H20 is rejected, assumes no difference 
between clazosentan and placebo in the proportion of subjects with a poor mRS score at 
Week 12 post-aSAH.  


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The alternative hypothesis H3a is that there is a difference between these arms: 
H30: p31 = p30 
vs 
H3a: p31 ≠ p30 
Here p30 and p31 denote the proportion of subjects with a poor mRS at Week 12 post-aSAH 
in the placebo and clazosentan arms, respectively. This hypothesis will be tested at a 
two-sided significance level of 0.05. 
Superiority will be concluded if the upper limit of the two-sided 95% CI for the relative 
risk of clazosentan compared to placebo is lower than 1. 
The fourth null hypothesis H40, which will be tested if H30 is rejected, assumes no 
difference between clazosentan and placebo in the proportion of subjects with a poor GOSE 
score at Week 12 post-aSAH.  
The alternative hypothesis H4a is that there is a difference between these arms: 
H40: p41 = p40 
vs 
H4a: p41 ≠ p40 
Here p40 and p41 denote the proportion of subjects with a poor GOSE at Week 12 post-aSAH 
in the placebo and clazosentan arms, respectively. This hypothesis will be tested at a 
two-sided significance level of 0.05. 
The study will be considered successful if the first null hypothesis (H10) is rejected. 
10.3.2 Analysis of the primary efficacy variable 
10.3.2.1 Hypotheses 
The null hypothesis (H0) is that the occurrence of clinical deterioration due to DCI in 
subjects treated with clazosentan is not different from placebo. The alternative hypothesis 
(HA) is that the event rate in the clazosentan arm differs from the placebo arm. 
10.3.2.2 Primary statistical analysis 
The primary statistical analysis will be performed on the FAS, according to the 
intent-to-treat approach. 
The null hypothesis will be tested using a CMH test stratified* on WFNS grade (1–2 vs  
3–5) and age (≤ 60 and > 60 years) at hospital admission at the two-sided significance level 
of alpha = 0.05. 
The treatment effect (clazosentan vs placebo) will be expressed in terms of odds ratios 
(ORs) and also in terms of relative risk reduction of the active arm compared to placebo 
with corresponding 95% CL. A relative risk lower than 1 will indicate a response to 
treatment in favor of clazosentan over placebo. The relative risk reduction, representing 
the difference in event rates relative to (or proportional to) the placebo event rate, expressed 


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as a percentage, will be calculated. A value lower than 100% will indicate a response in 
favor of clazosentan over placebo. 
Homogeneity of the treatment effect across strata* will be investigated using the 
Breslow-Day test.  
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. Due to the 
low number of subjects randomized in this stratum this variable will not be used as an adjustment variable 
and will be excluded from interaction testing and subgroup analyses. 
The incidence rates will be displayed together with the exact 95% CL (Clopper-Pearson). 
The treatment effect will be described, each with its 95% CL, with:  
• The absolute difference in the rates,  
• The odds ratio, 
• The relative risk and relative risk reduction. 
10.3.2.3 Handling of missing data 
Subjects randomized and treated 
The CEC will provide a final assessment (yes or no) on the primary endpoint, indicating 
for each subject whether it has been met, therefore it is assumed that there will not be any 
missing data for the primary endpoint. In addition, the CEC will distinguish between the 
cases of clinical deterioration due to DCI and the cases imputed according to the 
substitution rules described in Section 6.1.1.  
There will be no missing data for the variables included in the model since these variables 
are collected as stratification factors for the randomization. 
Subjects randomized but not treated 
No further data will be collected for these subjects. They will not be reviewed by the CEC 
and will be considered as having met the primary endpoint, i.e., the worst possible outcome 
is assumed in a sensitivity analysis. 
10.3.2.4 Supportive analyses 
This analysis uses a logistic regression model instead of the CMH test on the FAS. 
The primary endpoint follows a binomial distribution and the assessment of clazosentan 
15 mg/h treatment effect relative to placebo will be done using a logistic regression 
adjusting* for hospital admission WFNS grade (1–2 vs 3–5), and age (≤ 60 and > 60 years) 
at hospital admission. 
The linear model used for testing the treatment effect is described by: 


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log (p/(1-p)) = α + β1 * treatment + β2 * WFNS + β3 * age, 
where: 
• p refers to the probability of the event, 
• treatment refers to clazosentan 15 mg/h and placebo (reference is placebo), 
• WFNS refers to hospital admission WFNS grade (1–2 vs 3–5),  
• age (years) refers to that at hospital admission (continuous). 
The coefficients α, β1, β2 and β3 will be estimated by the method of maximum likelihood.  
Results of the logistic regression will be presented by the odds ratios, the corresponding 
95% Wald CL and the p-value derived from the Wald statistic (Type III analysis of effects). 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. Due to the 
low number of subjects randomized in this stratum this variable will not be used as an adjustment variable 
and will be excluded from interaction testing and subgroup analyses. 
The primary efficacy analysis planned in protocols up to version 5 will be performed as a 
supplementary analysis: i.e., the primary efficacy analysis described in Section 10.3.2.2 
will be repeated including the patient population (high-risk prevention vs early treatment) 
as an additional adjustment factor. 
10.3.2.5 Sensitivity analysis 
The CMH analysis will be repeated on the PPS in order to assess the impact of important 
protocol deviations on the assessment of the primary endpoint. This analysis will, in 
particular, address the issue of the lack of adherence to important protocol requirements or 
compliance with study treatment.  
The CMH analysis may also be repeated on the FAS, on the subset of subjects for which 
the primary endpoint was met based on the occurrence of clinical deterioration due to DCI 
in order to address the possible issue of unclear cases potentially linked to missing data. 
The CMH analysis may also be repeated on the Randomized analysis set. This analysis will 
only be conducted if the number of subjects randomized but not treated is greater than 5%. 
Additional sensitivity analyses will be specified in the SAP. 
10.3.2.6 Subgroup analyses 
The aim of these exploratory subgroup analyses, classifying subjects according to 
important baseline characteristics, is to explore the consistency of treatment effect in a 
variety of relevant subject subgroups to support the efficacy evaluation of clazosentan in 
this indication. 


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The study is stratified by the following subgroup variables: 
• WFNS grade at hospital admission (1–2 vs 3–5). 
• Patient population (high-risk prevention vs early treatment*). 
• Age (≤ 60 and > 60 years) at hospital admission. 
The following pre-specified subgroups may also be considered for the analyses (details 
will be provided in the SAP):  
• Geographical location. 
• Gender. 
• Type of aneurysm-securing procedure.  
Additional subgroup analyses for the primary endpoint may also be conducted for factors 
that would be identified with a statistically significant treatment  factor interaction*. 
Results of the subgroup analyses will be displayed in a forest plot and will include: 
1. An estimate of the treatment effect (OR for clazosentan vs placebo) with its 95% CL 
for each level of each subgroup. It will be calculated using the CMH estimator of the 
common OR obtained separately in each subgroup level as described for the main 
analysis.  
2. A vertical reference line displayed at the level of the overall treatment effect. 
The subgroup analyses will also be performed using a logistic regression model stratified* 
by WFNS grade and age at hospital admission and including terms for “subgroup”, 
“treatment” and “treatment by subgroup” interaction*. Results will be summarized in a 
table and will include: 
1. An estimate of the treatment effect (OR for clazosentan vs placebo) with its 95% CL 
for each level of each subgroup.  
2. A p-value for the interaction tests.  
The study is not designed or powered to detect interactions but an arbitrary two-sided 
significance level of alpha = 0.10 will be used for the interpretation of the interaction test. 
No multiplicity adjustment is introduced as the subgroup analyses are exploratory in nature. 
If there are issues due to very small sample sizes (e.g., interaction test failing due to 
presence of observed zero cells), the use of other methods may be considered. 
*Recruitment into the early treatment group was discontinued from protocol version 6 onwards. Due to the 
low number of subjects randomized in this stratum this variable will not be used as an adjustment variable 
and will be excluded from interaction testing and subgroup analyses. 


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10.3.3 Analysis of the secondary efficacy variables 
10.3.3.1 Occurrence of clinically relevant cerebral infarction at Day 16 post-study drug 
initiation defined as: all-cause cerebral infarction ≥ 5 cm3 or cerebral 
infarction < 5 cm3 in subjects with clinical deterioration due to DCI 
Hypotheses 
The null hypothesis (H0) is that the occurrence of clinically relevant cerebral infarction at 
Day 16 post-study drug initiation defined as: all-cause cerebral infarction ≥ 5 cm3 or 
cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI in subjects 
treated with clazosentan is not different from placebo. The alternative hypothesis (HA) is 
that the event rate in the clazosentan arm differs from the placebo arm. 
Primary statistical analysis 
The proportion of subjects with the main secondary endpoint will be analyzed in a similar 
manner as for the primary efficacy endpoint.  
The primary statistical analysis will be performed on the FAS, according to the 
intent-to-treat approach.  
Handling of missing data  
Subjects randomized and treated 
The CEC will provide a final assessment (yes or no) on the first component of the main 
secondary endpoint (infarcts ≥ 5 cm3), indicating for each subject whether it has been met 
and distinguishing between the true cases of cerebral infarction ≥ 5 cm3 and imputed cases 
(as per CEC charter). Regarding the second component, subjects who met the primary 
endpoint as per CEC but with missing CT scan at Day 16 will be considered to have met 
the secondary endpoint (i.e., the worst possible outcome is assumed). 
There will be no missing data for the variables included in the model since these variables 
are collected as stratification factors for the randomization. 
Subjects randomized and not treated 
No further data will be collected for these subjects. They will not be reviewed by the CEC 
and will be considered to have met the secondary endpoint, i.e., the worst possible outcome 
is assumed in a sensitivity analysis.  
Supportive analyses 
This analysis uses a logistic regression model instead of the CMH test on the FAS. It will 
be conducted in a similar manner as for the primary efficacy endpoint. 


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Sensitivity analyses 
The CMH analysis will be repeated on the PPS performed in order to assess the impact of 
important protocol deviations on the assessment of the primary endpoint. This analysis will 
in particular, address the issue about the lack of adherence to important protocol 
requirements or compliance to study treatment.  
In order to address possible issues of unclear cases that are potentially linked to missing 
data, the CMH analysis may also be repeated on a subset of subjects from the FAS for 
whom the secondary endpoint was met based on the occurrence of all-cause new or 
worsened cerebral infarction ≥ 5 cm3. 
The CMH analysis may also be repeated on the Randomized analysis set. This analysis will 
only be conducted if the number of subjects randomized but not treated is greater than 5%.  
Subgroup analyses 
Exploratory subgroup analyses may be conducted in the subgroups defined for the primary 
endpoint. 
10.3.3.2 Clinical outcome as assessed by the mRS at Week 12 post-aSAH 
Primary statistical analysis 
The proportion of subjects with a poor (score of 3 to 6) clinical outcome (mRS) at 
Week 12 post-aSAH will be analyzed in a similar manner as for the primary efficacy 
endpoint.  
Handling of missing data  
Subjects randomized and treated 
If the mRS score from the Week 12 interview is missing, and the subject did not die prior 
to Week 12, the missing mRS score is replaced by the score 4 (moderately severe 
disability), with the following exception: 
• If the subject had their mGCS score reported at least once per day, from study drug 
initiation up to 14 days post-study drug initiation, and all reported scores regardless of 
day and time point are ≥ 14, and the location the subject was discharged to after the 
initial hospitalization at the investigational study center is home, then the missing mRS 
is substituted with 2 (slight disability). 
Subjects randomized but not treated 
These subjects will not be observed up to Week 12 post-aSAH, therefore the worst possible 
outcome is assumed in a sensitivity analysis. If the subject is still alive at the time they 
withdraw from study, a missing mRS score will be replaced by the score 4 (moderately 
severe disability).  


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10.3.3.3 Clinical outcome as assessed by the GOSE at Week 12 post-aSAH 
Hypotheses 
The null hypothesis (H0) is that the proportion of subjects with poor clinical outcome 
treated with clazosentan is not different from placebo. The alternative hypothesis (HA) is 
that the event rate in the clazosentan arm differs from the placebo arm. 
Primary statistical analysis 
The proportion of subjects with a poor (score of 1 to 4) clinical outcome (GOSE) at 
Week 12 post-aSAH will be analyzed in a similar manner as for the primary efficacy 
endpoint. 
Handling of missing data  
Subjects randomized and treated 
If the GOSE score from the Week 12 interview is missing, and the subject did not die prior 
to Week 12, the missing GOSE score is replaced by the score 3 (lower severe disability), 
with the following exception: 
• If the subject had their mGCS score reported at least once per day, from study drug 
initiation up to 14 days post-study drug initiation, and all reported scores regardless of 
day and time point are ≥ 14, and the location the subject was discharged to after the 
initial hospitalization at the investigational study center is home, then the missing 
GOSE is substituted with 5 (lower moderate disability). 
Subjects randomized but not treated 
These subjects will not be observed up to Week 12 post-aSAH, therefore the worst possible 
outcome is assumed in a sensitivity analysis. If the subject is still alive at the time they 
withdraw from study, a missing GOSE score will be replaced by the score 3 (lower severe 
disability). 
Supportive analyses 
Logistic regression 
This analysis uses a logistic regression model instead of the CMH test on the FAS. It will 
be conducted in a similar manner as for the primary efficacy endpoint. 
Proportional odds regression model 
As ordinal analysis of outcome substantially increases statistical power, the proportional 
odds model will be used as a supportive analysis to assess treatment effect on GOSE data 
under the assumption that the OR for the treatment variable is the same for all possible 
ways of collapsing the ordinal outcome scale (i.e., GOSE) into a better and a worse 
category. The likelihood ratio test evaluates whether this odds ratio differs from 1.  


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Sensitivity analyses 
The CMH analysis will be repeated on the PPS performed in order to assess the impact of 
important protocol deviations on the assessment of this secondary endpoint.  
The CMH analysis may also be repeated on the Randomized analysis set. This analysis will 
only be conducted if the number of subjects randomized but not treated is greater than 5%.  
Subgroup analyses 
Exploratory subgroup analyses may be conducted in the subgroups defined for the primary 
endpoint. Additional analyses may also be conducted on predefined subsets such as 
subjects who had mGCS ≥ 14 and aNIHSS = 0 prior to study drug start. 
10.3.4 Analysis of other efficacy variables 
The analysis of all other efficacy variables will be described in detail in the SAP.  
The analysis of the effect of clazosentan on long-term clinical outcome, cognition, and 
health-related QoL at Week 12 post-aSAH will be, in particular, described through an 
integrated approach as subject-relevant outcomes.  
Other variables may also be analyzed by subgroups. Additional analyses, especially for the 
exploratory efficacy endpoints, may also be conducted on predefined subsets such as 
subjects who had mGCS ≥ 14 and aNIHSS = 0 prior to study drug start.  
Other efficacy endpoints will be analyzed at each relevant time point listed in the visit and 
assessment schedule see Table 1 and Table 2. 
10.3.5 Analysis of the safety variables 
The Safety analysis set will be used to perform all safety analyses. 
If not otherwise stated, only treatment-emergent safety data will be considered in tables 
and figures. All safety data will be included in listings, with flags for safety data considered 
to be treatment-emergent.  
Summaries of safety will be essentially reflected by descriptive statistics for each treatment 
arm.  
No statistical comparisons among the treatment arms with respect to any of the safety 
parameters will be performed. 
10.3.5.1 Adverse events 
TEAEs and serious adverse events 
TEAEs and SAEs will be tabulated by study treatment, system organ class (SOC) and 
preferred terms within each SOC: the number and percentage of subjects who experienced 


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at least one (S)AE, at least one (S)AE within each SOC and at least 1 (S)AE within each 
preferred term will be displayed. (S)AEs will also be summarized by decreasing frequency 
of preferred term and tabulated by maximum intensity and relationship to clazosentan or 
placebo. 
AEs leading to premature discontinuation of study drug 
(S)AEs leading to premature discontinuation of study drug will be summarized in a similar 
manner as that described above. 
TEAEs of specific interest 
They will be tabulated by study treatment, category (e.g., lung complications, hypotension, 
anemia) and preferred term within each category: the number and percentage of subjects 
who experienced at least one AE of specific interest within each preferred term will be 
displayed. 
Occurrence of rescue therapy-specific AEs up to hospital discharge  
They will be summarized in a similar manner as that described above. 
10.3.5.2 Laboratory data 
Changes from baseline in laboratory variables 
Descriptive summary statistics by visit and study treatment will be provided for observed 
values and absolute changes from baseline for laboratory tests (e.g., hematology, blood 
chemistry). 
Data will be displayed in SI units whenever possible and graphical approaches will be 
applied for certain variables.  
Treatment-emergent marked laboratory abnormalities 
Treatment-emergent marked laboratory abnormalities will be summarized descriptively by 
study treatment as categorical variables. 
10.3.6 Analysis of other variables 
A full description of all other analyses will be described in the SAP. 
10.4 Interim analyses 
No interim analyses are planned in this study. 
10.5 Sample size 
A total of approximately 400 subjects are planned for enrollment into this study and will 
be randomized according to a 1:1 ratio. Assuming a 10% drop-out rate, this should provide 
approximately 360 evaluable subjects. 


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10.5.1 Primary efficacy objective 
Data observed in previous studies in similar sets (placebo arm, high-risk population) 
showed an incidence rate of clinical deterioration due to DCI of 28%  
Under the assumption that the true incidence of events in placebo arm is 28% and in 
clazosentan arm is 14%, a sample size of n = 176 in each treatment arm will have 90% 
power to show the superiority in response of clazosentan compared to placebo using 
Pearson’s ² test with a 5% two-sided significance level. When taking an approximate 10% 
drop-out rate into account, 400 subjects have to be enrolled in the study, with n = 200 
randomized to each treatment arm. If the true incidence rate in the placebo arm is as low 
as 22% this sample size (N = 352) will still provide a power of 80% at alpha level of 5% 
to demonstrate a treatment effect of 50%. 
10.5.2 Secondary efficacy objective (main) 
This study includes an important endpoint that is the occurrence of clinically relevant 
cerebral infarction at Day 16 post-study drug initiation defined as: all-cause cerebral 
infarction ≥ 5 cm3 or cerebral infarction < 5 cm3 in subjects with clinical deterioration due 
to DCI. With this sample size (N = 352) and under the following assumptions, this study 
has 75% power to demonstrate a statistically significant reduction at alpha level of 5% 
two-sided between placebo and clazosentan arms from 20–10%. 
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timely reporting of subject data. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation and traceability 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). 
Entries recorded by the subject or the proxy, and/or the assessor (where applicable), on the 
paper copies of the MoCA, the GOSE, the SS-QOL, the Ox-PAC, and the EQ-5D are 
considered source data. Site personnel will review and ensure completeness of the subjects’ 
entries. 


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For each subject screened, regardless of subsequent randomization and 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. 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents submitted to the CEC or those attached to SAE forms / 
Pregnancy forms) submitted to the sponsor or 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 subject 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 access to the site eCRF 
data until the database is locked. 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. Should discrepant data be detected, a query specifying the matter 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 will be processed through a central laboratory 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 or its delegate. Medications are coded according to the latest WHO Drug 
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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 
appropriate sponsor QS docs. After database lock, the investigator will have read-only 
access to the site eCRF subject data, until receipt of an electronic copy of the site eCRFs 
(including the audit trail) on electronic media.  
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 
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/proxy. If the subject is not able to provide personal consent at the time the 
consent is obtained, then he/she must provide this consent as soon as possible once his/her 
clinical condition has improved to the extent that providing personal consent is possible, 
unless local regulations state otherwise. 
The investigator/delegate must explain to subjects/representatives/proxies that they are 
completely free to refuse to enter the study, or to voluntarily withdraw from the study at 


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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/representative/proxy to consider his or her decision to participate in the study 
and it shall be verified that the subject/representative/proxy has understood the information 
(e.g., by asking the subject/representative to explain what is going to happen). The ICF will 
be provided in the country’s local language(s). 
Site personnel authorized (according to local regulation and sponsor requirements) 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/representative/proxy 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 and are not part of 
routine standard of care) begin. 
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 clinical study report. IECs/IRBs will be 
provided with listings of protocol deviations as per local requirements. 


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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. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the 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 2 different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
the sponsor’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the site for any or all of the documents, 
special arrangements, respecting the data confidentiality, must be made between the 
investigator and the sponsor to store these documents outside the site, so that they can be 
retrieved in 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 personal and restricted access to 
the data for study subjects, 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 printouts must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies 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. 


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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 
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 as soon as possible after each of the study 
periods, and after each visit / telephone call / other contact, 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. 


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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. 
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. 


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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. 
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 clinical study report 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. 
All involved persons (including the coordinating investigator, if applicable), will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the study 
results with the sponsor personnel prior to submission to a peer-reviewed journal or 
presentation at a congress. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 
• substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• drafting of the publication or critical review for important intellectual content; and 
• providing final approval of the version to be published; and 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved. 
The list of authors of any publication of study results may include representatives of the 
sponsor and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
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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. 
13 REFERENCES 
[Clazosentan IB] Investigator’s Brochure for clazosentan, Version 17. Idorsia 
Pharmaceuticals Ltd, in preparation. 
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[Allen 1983] Allen GS, Ahn HS, Preziozi TJ, Battye R, Boone SC, Chou SN, et al. Cerebral 
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[Boosman 2010] Boosman H, Passier PE, Visser-Meily JM, Rinkel GJ, Post MW. 
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[Brilstra 2000] Brilstra EH, Rinkel GJ, Algra A, van Gijn J. Rebleeding, secondary 
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[Clozel 1993] Clozel M, Watanabe H. BQ-123, a peptidic endothelin ETA receptor 
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[Connolly 2012] Connolly ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 
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Association / American Stroke Association. Stroke. 2012;43(6):1711–37. 


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[Cosentino 1994] Cosentino F, Katusic ZS. Does endothelin-1 play a role in the 
pathogenesis of cerebral vasospasm? [review] Stroke. 1994;25(4):904–8. 
[Fergusen 2007] Fergusen S, Macdonald RL. Predictors of Cerebral Infarction in Patients 
with Aneurysmal Subarachnoid Hemorrhage. Neurosurgery. 2007;60(4):658–67. 
[Frontera 2009] Frontera J, Fernandez A, Schmidt JM, Claassen J, Wartenberg KE, 
Badjatia N, et al. Defining Vasospasm After Subarachnoid Hemorrhage What Is the 
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14 APPENDICES 
Appendix 1 
Definition of “thick and diffuse clot” on hospital admission CT scan 
A “thick and diffuse clot” is defined as a thick confluent clot, more than 4 mm in thickness, 
involving 3 or more basal cisterns. 
A basal cistern contains a thick clot, if SAH completely fills the cistern or a part of a larger 
cistern (e.g. Sylvian fissure) and is at least 4 mm in thickness measured along the shortest 
dimension. Care should be taken to not assess the clot thickness where the cistern is 
primarily in the axial plane as it will artificially increase the apparent thickness of the clot. 
A single isolated spot with 4 mm thick SAH is not sufficient to designate a cistern as “thick 
clot”. The clot should occupy a significant portion of the cistern. At least 3 cisterns must 
contain a thick clot. 
The following guidelines should be used to confirm that the subarachnoid blood in a basal 
cistern is thick: 
• SAH maintains a thickness of 4 mm or more over at least a 20 mm extent of the cistern.  
• The cistern appears expanded because of SAH. 
• There is a “negative” contrast with hyper-dense subarachnoid blood outlining 
subarachnoid structures. 
In order to determine the overall extent of the hemorrhage, the following basal cisterns (see 
below figure) must to be assessed at different levels (i.e., all contiguous slices from the 
inferior aspect of the brain stem to the most superior aspect of the Sylvian fissures), and at 
least 3 of the cisterns must contain a thick clot in order to be eligible for the study.  
• left Sylvian fissure (green) 
• right Sylvian fissure (green) 
• supra sellar cistern (red) 
• perimesencephalic cistern (yellow) 
• anterior inter-hemispheric fissure (blue) 
• prepontin cistern (not marked on the figure below) 
 
 




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Appendix 2 
Global vasospasm assessment 
Note: This appendix is only applicable to subjects recruited into the early treatment group. 
Recruitment into the early treatment group was discontinued from protocol version 6 
onwards. 
The presence/absence of vasospasm will be determined at the level of the proximal 
(vertebro basilar, intradural internal carotid artery [ICA], A1, M1 and P1) and distal (A2, 
P2 and M2) brain vessels. If vasospasm is present, its location and severity will be 
indicated. For distal vessels, vasospasm is only considered to be present if at least two 
branches are affected. If only one branch shows vasospasm, the segment is NOT considered 
to be affected by vasospasm.  
The severity of the vasospasm in each predefined vessel segment will be indicated based 
on the following 4 categories:  
1. None = No vasospasm 
2. Mild = up to 1/3 of vessel narrowing 
3. Moderate = more than 1/3 and up to 2/3 of vessel narrowing 
4. Severe = more than 2/3 of the vessel narrowing 
The location of the vasospasm will be indicated from among the following: 
• vertebro basilar 
• intradural ICA (Left/Right) 
• A1 (Left/Right) 
• A2 (Left/Right) 
• M1 (Left/Right) 
• M2 (Left/Right) 
• P1 (Left/Right) 
• P2 (Left/Right) 
For the assessment of global vasospasm, only the predefined vessels mentioned above are 
considered. Vasospasm that is present exclusively in the most distal parts (e.g., A3, A4, 
P3) should not be taken into account. 
The severity of global vasospasm will be indicated using the using the following 
definitions: 
• Moderate vasospasm: at least two segments with moderate vasospasm and/or one 
segment with severe vasospasm 
• Severe vasospasm: at least two segments with severe vasospasm 


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Anterior and Posterior Circulation Nomenclature 
Anterior Circulation 
 
Posterior Circulation 
 


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Middle Cerebral Artery (MCA) 
 M1: Pars sphenoidalis  
 M2: Pars insularis 
 M3: Pars horizontalis 
 M4: Pars terminalis  
 
Anterior Cerebral Artery (ACA) 
A1: Carotid terminus to Anterior  
Communicating artery (ACOM) 
 
 A2: ACOM to next bifurcation 
 
 
Posterior Cerebral Artery (PCA) 
 P1: Precommunicating segment  
 P2: Ambiens (circular) segment 
 P3: Quadrigeminal segment  
 P1 – P3: Pars circularis 
 P4: Pars corticalis 
 
Appendix 3 
Patient Management Guidelines  
It is expected that, wherever possible, the rules in the guidelines are followed. However, 
during the treatment period, individual subject characteristics and specific clinical 
situations may not always allow the strict adherence to these guidelines. Any deviation is 
to be documented in the subject’s source notes along with medical justification. Key 
measures of compliance with the Patient Management Guidelines will be checked by the 
sponsor or representative.  
1. Main objectives 
• To reduce the incidence of predictable and preventable AEs via information and 
proactive management.  
• To increase consistency and standardization in the level of care across all study sites 
for certain key clinical parameters. 
2. Background and rationale  
The safety profile of clazosentan has been well characterized based on the data 
accumulated from previously conducted Phase 2 and 3 clinical trials in which over 
1800 subjects with aSAH were treated with active drug, including over 300 subjects at the 
currently tested 15 mg/h dose. Certain AEs are associated with the administration of 
clazosentan, notably hypotension, lung complications (in particular pulmonary edema, 
pleural effusion, and respiratory failure) and anemia.  
When objective BP measurements were analyzed, the magnitude of the BP decrease was 
seen to be modest, in the order of 10%. Clazosentan has a systemic vasodilatory effect, 
common to ERAs.  


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Anemia is a class effect of ERAs, is believed to be related to hemodilution, and is typically 
reversible after discontinuation of clazosentan.  
Fluid retention is also a common finding with ERAs. An association between a positive 
cumulative fluid balance and the occurrence of lung complications has been observed 
previously in aSAH subjects, suggesting an important role of fluid management in the 
occurrence of these events.  
The above described events are either preventable or manageable in a typical ICU setting. 
Patient Management Guidelines that emphasize the maintenance of euvolemia and target 
BP goals, are expected to decrease the incidence of lung complications related to fluid 
retention and hypotension and to facilitate their management in the event they should 
occur. 
Study drug must therefore be administered in parallel to vasopressors and fluids, as needed, 
and must not be initiated until BP is adequately controlled according to the below 
guidelines. Similarly, vasopressor and fluid therapy should not be discontinued until after 
the discontinuation of study drug.  
During the study treatment period, all subjects must be in an ICU (or equivalent 
environment where all protocol assessments can be performed and these Patient 
Management Guidelines followed) with strict BP monitoring. 
Prior to enrolling a subject into the study, BP and fluid status must be controlled, as needed, 
with i.v. vasopressors and fluid administration according to these guidelines. Conditions 
contraindicating increased doses of vasopressors are described in these guidelines 
(see General BP Control) and if present at the time of enrollment, investigator judgment is 
required regarding the suitability of the subject for the study.  
3. Fluid management  
3.1 General fluid monitoring and control 
The goal of the following recommendations is to emphasize euvolemia to avoid fluid 
overload.  
Central venous monitoring is highly recommended in all subjects, for enabling 
administration of vasopressors, fluids, and CVP measurement.  
Maintenance of i.v. fluid administration 
• Administer 
saline, 
Ringer’s 
Lactate, 
or 
a 
balanced 
crystalloid 
solution 
(e.g., Isofundine®, Plasma-Lyte®, Stereofundin®) starting at 1.0 to 1.5 mL/kg/h. This 
hourly infusion rate should include the volume of fluid administered with the study 
drug and be adjusted based on other i.v. administered products.  


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• Evaluate for the presence or absence of euvolemia.  
Indicators of euvolemia include:  
1. Total 24-hour fluid output is well matched to fluid input (i.e., within 500 mL/day)  
2. Inferior vena cava (IVC) is non-collapsible with spontaneous respirations 
(< 40% fluctuation in diameter as observed on echocardiography) off the ventilator circuit  
3. A 15% or less increase in IVC diameter (as observed on echocardiography) with 
inspiration in mechanically-ventilated subjects given a tidal volume of 10 mL/kg with a 
PEEP of 0 cm H20  
4. Stroke volume variability (SVV) is < 10% (using Cheetah NICOM®, Edwards FloTrac®, 
PiCCO®, or another advanced circulatory monitoring device) 
5. Increase in stroke volume to passive leg raising is < 10% (measured with a hemodynamic 
monitoring device) 
 
 
The passive leg-raising test consists of measuring the hemodynamic effects of a leg 
elevation up to 45°. A simple way to perform the postural maneuver is to transfer the 
subject from the semi-recumbent posture to the passive leg-raising position by using the 
automatic motion of the bed. 
Conversely, the potential for hypovolemia is assessed by fluid-responsiveness indicators 
which are the following: 
1. IVC collapses > 40% with respiratory cycle off ventilator circuit  
2. CVP ≤ 5 mmHg off ventilator circuit  
3. SVV is > 10% with respiratory cycle (measured with Cheetah NICOM®, Edwards 
FloTrac®, PiCCO®, or a similar hemodynamic monitoring device)  


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4. Passive leg raising to 45° results in a > 10% increase in left ventricular stroke volume 
(measured with a hemodynamic monitoring device), a > 10% increase in arterial pulse 
pressure (measured via arterial line), or a 5% increase in ETCO2 (end-tidal CO2).  
Of note, a positive fluid responsiveness does not necessarily mean extra fluids are required. 
The absence of fluid responsiveness usually indicates that extra fluids are not required. 
Administer a crystalloid or colloid fluid bolus if, and only if, there is evidence of potential 
fluid-responsive hypotension.  
Warning: Administration of large fluid boluses (≥ 1 liter cumulatively over 24 hours) to 
subjects not documented to be fluid-responsive must be avoided. The reason for 
administering fluid boluses with a cumulative volume of > 1 liter over 24 hours or any total 
24-hour fluid input of > 4 liters (or > 60 mL/kg/day, if greater) must be documented in the 
source notes. For subjects with a urine catheter, a positive fluid balance of more than 
1000 mL over at least two consecutive days is to be justified in the subject’s medical chart.  
3.2 
Permanent study drug discontinuation due to fluid retention 
Due to the potential for clazosentan to induce fluid retention, the occurrence of generalized 
brain edema as well as severe pulmonary edema should result in the permanent 
discontinuation of study drug.  
4. Blood pressure management 
4.1 General BP control  
The goal of the following recommendations is to optimize BP by the preferential 
administration of vasopressors to avoid excessive administration of fluids. Fluid 
administration should not exceed that which is described in the Fluid Management section 
of these guidelines.  
1. BP measurements obtained in the supine position by arterial line or noninvasive cuff 
(sphygmomanometer) are both acceptable. However, the same modality should be used 
consistently for each BP measurement for a given subject.  
2. In the absence of vasospasm or in the presence of asymptomatic vasospasm (i.e., 
angiographic vasospasm without obvious clinical symptoms of vasospasm), the minimum 
target SBP should be 120 mmHg or higher. This guideline applies for most of the cases. 
However, it is acknowledged that in some instances, the subject’s known normal BP may 
be lower than this. If this is the case, then the target SBP should be the subject’s usual SBP.  
3. In the presence of symptomatic cerebral vasospasm, the minimum target SBP is 
150 mmHg, or higher as needed, with the target SBP titrated against clinical response. If 


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the target SBP cannot be met because the subject’s baseline (normal) BP is low, then the 
target SBP should be a 30% increase from the baseline SBP.  
If the target SBP is not already achieved spontaneously, BP should be raised by 
administering vasopressors unless specifically contraindicated. If BP is below the defined 
targets with more than 10% for more than 3 consecutive hours, the underlying reason is to 
be documented in the subject’s source notes.  
Contraindications to increasing the dose of vasopressors include heart failure (due to 
pre-existing cardiac disease or myocardial injury in the context of aSAH) in which case the 
increase in BP should be balanced against the decrease in cardiac output due to increased 
cardiac afterload, significant cardiac arrhythmias, pulmonary edema, and clinical or 
biological evidence of hypoperfusion (e.g., increase in serum lactate and creatinine). 
The dosing of oral or i.v. nimodipine (if applicable) should be adjusted according to local 
standard practice if the above target BPs cannot be met or maintained adequately. Consider 
temporarily interrupting or permanently discontinuing nimodipine as appropriate. 
If the target BP is already achieved spontaneously without requiring medical intervention, 
the potential need for vasopressors should be anticipated and the appropriate measures put 
into place to ensure their rapid initiation should the need arise.  
4.2 Hypotension management  
Automatic administration of bolus i.v. fluids in this scenario is discouraged unless there is 
compelling evidence that the subject is fluid responsive.  
Bedside clinical assessment should occur and intervention should be implemented in the 
following order:  
1. Ensure that lines administering vasopressors are patent and flowing.  
2. Adjust the dose of nimodipine (if applicable) and titrate the dose of vasopressor(s) 
upward until maximum dose is achieved.  
3. If SBP does not reach the target pressure despite maximal vasopressor therapy and 
adjustment/discontinuation of nimodipine, study drug should be discontinued temporarily. 
Study drug may be restarted when the SBP stabilizes above the target. If the hypotension 
is refractory and suspected to be related to study drug, the study drug should be 
permanently discontinued.  
4. Recommended vasopressors: phenylephrine or norepinephrine (noradrenaline). 
Epinephrine (adrenaline) and dopamine use is discouraged (due to the unpredictable effect 
on BP with dopamine and its potential to cause severe tachycardia, and the potential for 
severe arrhythmias with epinephrine).  


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5. In the event that the SBP goals are not reached or maintained, “fluid responsiveness” 
should be checked (see above under fluid management section). 
5. Mechanical ventilation considerations  
With low response to increased O2 administration and/or PEEP, be aware of the possibility 
of pulmonary ventilation/perfusion ratio mismatch:  
• If suspicion of this phenomenon is present, standard approaches to countering hypoxia 
should be applied. However, PEEP and FiO2 should not be continuously increased 
beyond the usual ranges.  
• If the condition does not improve, nimodipine should be stopped to check for signs of 
improvement. If the condition improves, then nimodipine should be discontinued 
permanently. If no improvement is seen after a couple of hours, it is left to the 
appreciation of the investigator to restart nimodipine or not. Study drug should then be 
temporarily interrupted to check for any potential relationship. If the condition is 
suspected to be related to study drug, then study drug should be permanently 
discontinued.  
6. General patient management 
Continuous ECG monitoring in the ICU is mandatory for the period of study drug 
administration. It is expected that each site will have a standard protocol in place, which 
will be adhered to for the following: 
• Fever management (i.e., temperature  38 °C/100 °F) 
• Gastro-intestinal bleeding prophylaxis (e.g., ranitidine) 
• Deep vein thrombosis prophylaxis (e.g., heparin 5000 units subcutaneously q12h or 
enoxaparin 40 mg subcutaneously once daily) 
• Serum glucose monitoring and control 
 
 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
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18 February 2022, page 164/182 
Confidential 
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Doc No D-22.069 
 
 
 
Appendix 4 
Glasgow Outcome Scale (extended version) and Modified Rankin 
Scale  
Glasgow Outcome Scale – Extended (GOSE) 
Modified Rankin Scale (mRS) 


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Structured Interview for the Extended Glasgow Outcome Scale and the Modified 
Rankin Scale 


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Doc No D-22.069 
 
 
 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
Final Version 7 
18 February 2022, page 167/182 
Confidential 
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Doc No D-22.069 
 
 


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Protocol ID-054-304, REACT 
Final Version 7 
18 February 2022, page 168/182 
Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 
 
 
 


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Protocol ID-054-304, REACT 
Final Version 7 
18 February 2022, page 169/182 
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EudraCT 2018-000241-39 
Doc No D-22.069 
 
 


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Protocol ID-054-304, REACT 
Final Version 7 
18 February 2022, page 170/182 
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Calculation of Glasgow Outcome Scale (extended) and Modified Rankin Scale scores 
GOSE and mRS scores will be derived by the interviewer from the responses to the 
individual interview questions following the rules detailed below: 


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Appendix 5 
Montreal Cognitive Assessment 


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Appendix 6 
Stroke Specific Quality of Life 


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18 February 2022, page 175/182 
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Protocol ID-054-304, REACT 
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18 February 2022, page 176/182 
Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 


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Aneurysmal subarachnoid hemorrhage 
Protocol ID-054-304, REACT 
Final Version 7 
18 February 2022, page 177/182 
Confidential 
EudraCT 2018-000241-39 
Doc No D-22.069 
 
 


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Doc No D-22.069 
 
 
 
Appendix 7 
EQ-5D (5L) 
 


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Doc No D-22.069 
 


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SAP_001.pdf: 
Cover page 
ID-054-304 
 
Statistical Analysis Plan 
 
 
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: 
26 January 2023 


 
 
 
 
 
CLAZOSENTAN (ACT-108475) 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
FOR CLINICAL STUDY REPORT 
 
ID-054-304 
 
REACT 
 
pRevention and trEatment of vAsospasm with ClazosenTan  
 
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) 
 
 
Version 4 
 
Document Number: D-23.039 
 
 
26 January 2023 
 
 
 
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 ............................................................7 
1 
INTRODUCTION .........................................................................................................9 
2 
STUDY DESIGN AND FLOW ....................................................................................9 
2.1 
Study design ...................................................................................................9 
2.2 
Study visit and assessment schedule ............................................................10 
2.3 
Overview of analysis periods .......................................................................11 
3 
OBJECTIVES .............................................................................................................11 
3.1 
Primary objective ..........................................................................................11 
3.2 
Secondary objectives ....................................................................................12 
3.3 
Other objectives ............................................................................................12 
4 
ANALYSIS SETS .......................................................................................................12 
4.1 
Definitions of analysis sets ...........................................................................12 
4.1.1 
Screened analysis set ........................................................................12 
4.1.2 
Randomized analysis set ...................................................................12 
4.1.3 
Full analysis set .................................................................................12 
4.1.4 
Safety analysis set .............................................................................13 
4.2 
Usage of the analysis sets .............................................................................13 
5 
STUDY SUBJECT VARIABLES AND ANALYSES ...............................................13 
5.1 
Subject disposition ........................................................................................14 
5.1.1 
Screening failures .............................................................................14 
5.1.2 
Study completion/discontinuation ....................................................14 
5.1.3 
Study treatment completion/discontinuation ....................................15 
5.2 
Protocol deviations .......................................................................................15 
5.3 
Analysis sets .................................................................................................15 
5.4 
Subject characteristics ..................................................................................15 
5.4.1 
Demographics ...................................................................................15 
5.4.2 
Baseline disease characteristics ........................................................16 
5.4.2.1 
Stratification factors ................................................................16 
5.4.2.2 
WFNS, total Glasgow Coma Scale score and motor deficit at 
hospital admission ...................................................................16 
5.4.2.3 
Neurological scales after admission and prior to Study drug 
initiation ...................................................................................17 
5.4.2.4 
aSAH-related characteristics ...................................................17 
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5.4.3 
Other baseline characteristics ...........................................................18 
5.4.3.1 
Computed tomography scan results ........................................18 
5.4.4 
Medical history and concomitant diseases and/or diagnoses ............19 
5.4.5 
Previous and concomitant therapies .................................................20 
5.4.5.1 
Previous/concomitant medications ..........................................20 
5.4.5.2 
Non-drug treatments/interventions ..........................................21 
5.4.5.3 
Rescue therapies ......................................................................21 
5.5 
Study treatment exposure and compliance ...................................................23 
5.5.1 
Exposure ...........................................................................................23 
5.5.2 
Compliance with study treatment .....................................................24 
6 
EFFICACY VARIABLES AND ANALYSES ...........................................................24 
6.1 
Overview ......................................................................................................24 
6.1.1 
Overall testing strategy .....................................................................25 
6.1.2 
Estimands ..........................................................................................26 
6.1.3 
Overview of primary and secondary efficacy analyses 
including subgroups ..........................................................................34 
6.2 
Primary endpoint ..........................................................................................35 
6.2.1 
Variable .............................................................................................35 
6.2.2 
Intercurrent events for the main estimand ........................................36 
6.2.3 
Handling of missing data ..................................................................36 
6.2.4 
Hypothesis, statistical model and assumptions .................................37 
6.2.5 
Main analysis ....................................................................................37 
6.2.6 
Supportive analyses ..........................................................................37 
6.2.6.1 
Logistic regression ..................................................................37 
6.2.6.2 
Rescue therapy for non-relevant vasospasms ..........................38 
6.2.6.3 
Deterioration due to DCI (based on neuroscales only) and 
death ........................................................................................38 
6.2.7 
Subgroup analyses ............................................................................38 
6.2.8 
Other analyses ...................................................................................40 
6.3 
Main secondary endpoint ..............................................................................40 
6.3.1 
Variable .............................................................................................40 
6.3.2 
Intercurrent events for the main estimand ........................................41 
6.3.3 
Handling of missing data ..................................................................41 
6.3.4 
Hypothesis, statistical model and assumptions .................................42 
6.3.5 
Main analysis ....................................................................................42 
6.3.6 
Supportive analyses ..........................................................................42 
6.3.7 
Subgroup analyses ............................................................................42 
6.3.8 
Other analyses ...................................................................................43 
6.4 
Other secondary endpoint .............................................................................43 
6.4.1 
Modified Rankin Scale .....................................................................43 
6.4.1.1 
Variable ...................................................................................43 
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6.4.1.2 
Intercurrent events for the main estimand ...............................43 
6.4.1.3 
Handling of missing data .........................................................44 
6.4.1.4 
Hypothesis, statistical model and assumptions .......................44 
6.4.1.5 
Main analysis ...........................................................................44 
6.4.1.6 
Supportive/sensitivity analyses ...............................................45 
6.4.1.7 
Subgroup analyses ...................................................................45 
6.4.1.8 
Other analyses .........................................................................45 
6.4.2 
Glasgow Outcome Scale – Extended ................................................46 
6.4.2.1 
Variable ...................................................................................46 
6.4.2.2 
Intercurrent events for the main estimand ...............................46 
6.4.2.3 
Handling of missing data .........................................................46 
6.4.2.4 
Hypothesis, statistical model and assumptions .......................47 
6.4.2.5 
Main analysis ...........................................................................47 
6.4.2.6 
Supportive/sensitivity analyses ...............................................47 
6.4.2.7 
Subgroup analyses ...................................................................48 
6.4.2.8 
Other analyses .........................................................................48 
6.5 
Subject-reported endpoints ...........................................................................48 
6.5.1 
Montreal Cognitive Assessment .......................................................49 
6.5.1.1 
Variables ..................................................................................49 
6.5.1.2 
Analysis ...................................................................................49 
6.5.2 
EQ-5D-5L .........................................................................................51 
6.5.2.1 
Variables ..................................................................................51 
6.5.2.2 
Analysis ...................................................................................51 
6.5.3 
Ox-PAQ ............................................................................................52 
6.5.3.1 
Variables ..................................................................................52 
6.5.3.2 
Analysis ...................................................................................53 
6.5.4 
Stroke-Specific Quality of Life .........................................................53 
6.5.4.1 
Variables ..................................................................................53 
6.5.4.2 
Analysis ...................................................................................54 
6.6 
Multivariate long-term outcome ...................................................................55 
6.6.1 
Variables ...........................................................................................55 
6.6.2 
Analysis ............................................................................................55 
6.7 
Analysis of pharmaco-economic variables ...................................................56 
6.7.1 
Rescue therapies ...............................................................................56 
6.7.2 
Specific (pre-specified) medical treatments and therapies ...............56 
6.7.3 
Subject location/rehabilitation ..........................................................56 
6.7.3.1 
Variables ..................................................................................56 
6.7.3.2 
Analysis ...................................................................................57 
6.7.4 
Employment status ............................................................................57 
6.7.4.1 
Assessments .............................................................................57 
6.7.4.2 
Variables ..................................................................................58 
6.7.4.3 
Analysis ...................................................................................58 
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6.8 
Biomarker endpoints analysis .......................................................................58 
6.8.1 
Variables ...........................................................................................59 
6.8.2 
Analysis ............................................................................................59 
7 
SAFETY VARIABLES AND ANALYSES ...............................................................59 
7.1 
Adverse events ..............................................................................................59 
7.1.1 
Variables ...........................................................................................60 
7.1.2 
Analysis ............................................................................................62 
7.2 
Laboratory tests ............................................................................................64 
7.3 
Electrocardiography ......................................................................................65 
7.4 
Vital signs .....................................................................................................66 
7.5 
Other safety variables and analyses ..............................................................66 
7.5.1 
Fluid balance .....................................................................................66 
7.6 
Subgroup analysis of safety variables ..........................................................67 
8 
GENERAL STATISTICAL METHODOLOGY ........................................................67 
9 
INTERIM ANALYSES AND DATA MONITORING COMMITTEES ...................67 
10 GENERAL DEFINITIONS AND DERIVATIONS ...................................................68 
10.1 
Handling of missing date ..............................................................................68 
10.2 
General analysis variables ............................................................................68 
10.3 
Study treatment administration error ............................................................69 
10.4 
Other derivations ..........................................................................................69 
11 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................70 
11.1 
Changes in the conduct of the study / data collection ..................................70 
11.2 
Changes to the analyses planned in the study protocol ................................70 
11.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................71 
11.4 
Additional analyses to those planned in the study protocol .........................72 
12 LIST OF TABLES, LISTINGS AND FIGURES .......................................................72 
13 REFERENCES ............................................................................................................72 
14 APPENDICES .............................................................................................................74 
14.1 
Revision History ...........................................................................................74 
14.2 
Schedule of events ........................................................................................76 
14.3 
Change from pre-aSAH to post-aSAH status ...............................................82 
14.4 
Adverse events of special interest ................................................................83 
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14.5 
Definitions of marked abnormalities ..........................................................112 
 
 
LIST OF TABLES 
 
Table 1 
Study committees ........................................................................................ 9 
Table 2 
Overview of the different analysis sets and their usage ............................ 13 
Table 3 
Definition of categories for reporting previous/concomitant 
medications ................................................................................................ 20 
Table 4 
Definition of categories for rescue therapies ............................................. 22 
Table 5 
Estimands for efficacy endpoints .............................................................. 29 
Table 6 
Overview of primary and secondary efficacy planned analyses, 
including subgroups .................................................................................. 34 
Table 7 
Imputation rules for an incomplete or missing AE datetime .................... 60 
Table 8 
Summary of adverse event analyses .......................................................... 62 
Table 9 
Marked abnormalities in laboratory parameters for reporting ................ 112 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design for the high-risk prevention group ....................................... 10 
Figure 2 
Study design for the early treatment stratum ............................................ 10 
 
 
 
 
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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
aNIHSS  
Abbreviated National Institutes of Health Stroke Scale 
ANOVA  
Analysis of variance 
aSAH  
Aneurysmal subarachnoid hemorrhage 
AST  
Aspartate aminotransferase 
CEC  
Clinical Event Committee 
CI  
Confidence interval 
CMH  
Cochran-Mantel-Haenszel 
CSR  
Clinical study report 
CT  
Computed tomography 
DCI  
Delayed cerebral ischemia 
eCRF  
Electronic case report form 
EOS  
End-of-Study 
FAS  
Full analysis set 
GCS  
Glasgow Coma Scale 
GOSE  
Glasgow Outcome Scale – Extended 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
ICU  
Intensive care unit 
IDMC  
Independent Data Monitoring Committee 
IE  
Intercurrent event 
IRC  
Independent Radiology Committee 
IRT  
Interactive Response Technology 
MedDRA  
Medical Dictionary for Regulatory Activities 
mGCS  
Modified Glasgow Coma Scale 
MLA  
Marked laboratory abnormality 
MoCA  
Montreal Cognitive Assessment 
mRS  
Modified Rankin Scale 
OR  
Odds ratio 
Ox-PAQ  
Oxford Participation and Activities Questionnaire 
PCA  
Principal Component Analysis 
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POM  
Proportional odds model 
PT  
Preferred Term 
QoL  
Quality of life 
RND  
Randomized analysis set 
RR  
Relative risk 
RRR  
Relative risk reduction  
SAE  
Serious adverse event 
SAF  
Safety analysis set 
SAP  
Statistical analysis plan 
SCR  
Screened analysis set 
SI  
Standard International 
SOC  
System Organ Class 
SS-QoL  
Stroke-Specific Quality of Life 
TEAE  
Treatment-emergent adverse event 
VAS  
Visual analog scale 
WFNS  
World Federation of Neurological Societies 
WHO  
World Health Organization 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes in detail the analyses and data presentation 
for the final clinical study report (CSR) for study ID-054-304 (REACT). Version 4 of the 
SAP is based on protocol version 7, dated 18 February 2022 [D-22.069] and replaces the 
previous SAP version 3, dated 27 September 2022. A revision history of the SAP is 
provided in Appendix 14.1. 
Obvious corrections to address minor formatting errors or spelling mistakes may be 
performed at the time of analysis without amending this and related documentation (e.g., 
mock shells).  
The study includes the study committees displayed in Table 1, each having a specific role. 
Table 1 
Study committees 
Committee 
Responsibility 
Independent Data Monitoring 
Committee 
Reviewing unblinded safety and efficacy data obtained in the study at 
regular intervals, and making appropriate recommendations based on 
the reported data. 
Independent Radiology 
Committee 
Reviewing retrospectively (during the course of the study) the 
angiograms and CT scans submitted for each randomized subject to 
determine the presence of pre-defined radiological features and to 
perform required measurements. 
Clinical Event Committee 
Determining, based on a charter, whether the primary and main 
secondary endpoint (first component, see Section 6.3.1 for details) 
have been met. 
CT = computed tomography. 
 
2 
STUDY DESIGN AND FLOW 
2.1 Study design 
This is a prospective, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, Phase 3 study. 
Subjects will be randomized 1:1 to clazosentan 15 mg/h or placebo, stratified by their 
World Federation of Neurological Societies (WFNS) grade at hospital admission (I–II vs 
III–V), patient population (high-risk prevention vs early treatment), and age at hospital 
admission (≤ 60 and > 60 years). Recruitment into the early treatment stratum was 
discontinued from protocol version 6 (29 April 2021) onwards.  
Overall, the study will enroll 400 subjects in 2 treatment groups, 200 subjects per group. 
The study will be conducted at approximately 100 sites in 15 countries. 
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Once randomized, the subjects will enter a double-blind treatment period of a maximum 
duration of 14 days. This will be sequentially followed by a safety follow-up period of 
24 hours and an extended follow-up period for safety and efficacy assessment terminating 
with an End-of-Study (EOS) visit at Week 24 post aneurysmal subarachnoid hemorrhage 
(aSAH).  
The overall study design for the high-risk prevention group is depicted in Figure 1. 
Note: The study design of the early treatment stratum is provided in Figure 2 although 
recruitment into this group was discontinued from protocol version 6 onwards.  
Figure 1 
Study design for the high-risk prevention group 
 
Figure 2 
Study design for the early treatment stratum 
 
2.2 Study visit and assessment schedule 
The study periods and ‘visits’ with their respective time windows are listed in the Visit and 
assessment schedules [see Appendix 14.2].  
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2.3 Overview of analysis periods 
An overview of the study periods and ‘visits’ is provided below.  
The study comprises the following consecutive periods: 
Screening period: Starts with the signature of the informed consent form (ICF) and ends 
with subject randomization. 
Treatment period: Starts immediately with the baseline assessments followed by the 
initiation of study drug infusion and ends with the permanent discontinuation of study drug.  
Observation period for the primary endpoint: This period covers the interval over 
which the subject may qualify for the primary endpoint of the study. It starts with the 
initiation of study drug infusion and ends on and includes Day 14 post-study drug initiation.  
24-hour safety follow-up period: Starts with the permanent discontinuation of study drug 
and ends 24 hours later.  
The End-of-Treatment assessments are included in the 24-hour safety follow-up period. 
These assessments are performed within 2 hours following permanent discontinuation of 
study drug.  
Extended follow-up period: Starts after the 24-hour safety follow-up period and ends with 
the EOS visit, occurring 24 weeks after the aSAH. 
EOS (individual subject): This is defined as the last visit performed for the study (i.e., the 
EOS visit, performed 24 weeks after the aSAH), or the date of premature discontinuation 
from the study, if applicable. 
EOS (study level): This time point occurs when the last subject completes his/her EOS 
visit. 
3 
OBJECTIVES 
The overall objective of this study is to determine the clinical efficacy of clazosentan in a 
population at high risk of developing ischemic complications post-aSAH, and to further 
evaluate its safety and tolerability in this population. 
3.1 Primary objective 
To determine the efficacy of clazosentan in preventing clinical deterioration due to delayed 
cerebral ischemia (DCI) in subjects with aSAH. 
Efficacy will primarily be assessed based on a reduction in the clazosentan group compared 
to the placebo group in the occurrence of clinical deterioration due to DCI up to 14 days 
post-study drug initiation. 
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3.2 Secondary objectives 
• To evaluate the effect of clazosentan on the occurrence of clinically relevant cerebral 
infarction at Day 16 post-study drug initiation defined as: 
– all-cause cerebral infarction ≥ 5 cm3 or 
– cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI.  
• To evaluate the effect of clazosentan on long-term clinical outcome, cognition, and 
health-related Quality of Life (QoL) at Week 12 post-aSAH and QoL at Week 24 
post-aSAH. 
• To evaluate the safety and tolerability of clazosentan in the selected population up to 
24 hours post-study drug discontinuation. 
3.3 Other objectives 
To evaluate the effect of clazosentan on healthcare resource utilization.  
4 
ANALYSIS SETS 
4.1 Definitions of analysis sets 
4.1.1 Screened analysis set 
The Screened analysis set (SCR) includes all subjects for whom informed consent to 
participate in the study has been obtained and who have a subject identification number.  
4.1.2 Randomized analysis set 
The Randomized analysis set (RND) comprises all subjects who have been assigned to a 
study treatment. 
4.1.3 Full analysis set 
The Full analysis set (FAS) comprises all subjects from the RND who started the study 
treatment. The rationale for this choice of the FAS is that, per study design, due to the 
emergency setting, the investigator has the possibility to withdraw subjects from the study 
before study drug initiation for safety or other reasons (e.g., due to a sudden deterioration 
of the clinical status post randomization). Defining the FAS as all subjects who have started 
study treatment is expected to preserve the intent-to-treat principle, because: a) randomized 
but untreated subjects will be rare (in previous Phase 3 studies, i.e., CONSCIOUS-2 and -3, 
less than 1% of the randomized subjects were not treated), and b) the decision whether or 
not to begin treatment cannot be influenced by knowledge of the assigned treatment.  
To adhere to the intent-to-treat principle, if not otherwise stated subjects will be evaluated 
according to their assigned study treatment (which might differ from the actual treatment 
received) and stratum information as recorded in the Interactive Response Technology 
(IRT) system. 
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4.1.4 Safety analysis set 
The Safety analysis set (SAF) comprises all subjects who have been assigned to a study 
treatment and who have started the study drug.  
Subjects will be evaluated according to the actual treatment they received, which may 
differ from the randomly assigned treatment.  
In the event of an administration error, i.e., a subject was administered both placebo and 
active treatment, the subject will be analyzed as ‘active treatment’ (‘clazosentan’).  
4.2 Usage of the analysis sets 
If not otherwise stated, the listings will be produced on the FAS for efficacy and on the 
SAF for safety. 
For the tables and figures, the sets are indicated in Table 2. 
Table 2 
Overview of the different analysis sets and their usage 
 
Analysis sets 
Analyses 
SCR 
RND 
FAS 
SAF  
Subject disposition,  
X 
X 
 
 
Analysis sets 
 
 
X 
X 
Protocol deviations  
 
[x] 
X 
 
Demographics characteristics 
 
[x] 
X 
[y] 
Baseline disease characteristics 
 
[x] 
X 
[y] 
Medical history and current medical conditions 
 
[x] 
X 
 
Previous and concomitant therapies 
 
[x] 
X 
 
Study treatment exposure 
 
 
 
X 
Primary efficacy endpoint 
 
[x] 
X 
 
Secondary efficacy endpoints 
 
[x] 
X 
 
Exploratory efficacy endpoint 
 
 
X 
 
Quality of life endpoints 
 
 
X 
 
Pharmaco-economic endpoints 
 
 
X 
 
Biomarker endpoints 
 
 
X 
 
Safety endpoints 
 
 
 
X 
Note: X: main analysis set; [x]: if RND and FAS differ by more than 5%, some tables may be replicated on the RND; 
[y]: if FAS and SAF differ by more than 5%, some tables may be replicated on the SAF. 
FAS = Full analysis set; RND = Randomized analysis set; SAF = Safety analysis set; SCR = Screened analysis set. 
 
5 
STUDY SUBJECT VARIABLES AND ANALYSES 
A listing of the randomization scheme and codes will be produced for randomized subjects 
only (as per ICH E3 16.1.7).  
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The analyses defined in this section on the FAS will be repeated on the RND if the RND 
and FAS differ by more than 5%. 
5.1 Subject disposition 
An overview of the recruitment for each country/site will be presented for the SCR and 
will comprise the following variables: 
• N (%) of subjects screened overall 
• N (%) of subjects randomized 
An overview of the number of subjects randomized in each treatment group (according to 
the assigned treatment group) and overall for each country/site will be presented for the 
RND. 
An overview of subject disposition over the course of the study will be presented for the 
RND in a table by treatment group (except for Screened, which is only summarized for the 
total column) and overall, and comprises the following variables: 
• N (%) of randomized subjects 
• N (%) of treated subjects 
• N (%) of subjects who completed the study treatment 
• N (%) of subjects who prematurely discontinued the study treatment 
• N (%) of subjects who completed the study 
• N (%) of subjects who prematurely discontinued the study 
A listing will be produced with the subjects randomized but not treated. 
5.1.1 Screening failures 
The number and percentage of subjects who failed screening and the reasons for screening 
failure will be summarized for the SCR (Overall). All reasons for screening failure will be 
included in a listing together with the screening failure date. An additional listing will 
present the list of eligibility criteria not met for the screened set where the screen-failed 
subjects will be flagged. 
5.1.2 Study completion/discontinuation  
The reasons for study discontinuation will be tabulated by treatment group and overall on 
the randomized set. 
A listing will be produced for all the subjects of the FAS who discontinued the study. It 
will display the EOS date, the EOS day (relative to start of study treatment), and the reason 
for discontinuation from the study.  
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5.1.3 Study treatment completion/discontinuation 
The reasons for treatment discontinuation as collected in the study treatment infusion log 
in the electronic case report form (eCRF) will be tabulated by treatment group and overall 
on the FAS. 
Subjects who prematurely discontinued the study treatment and subjects randomized but 
not treated are also included in the listing described in Section 5.1.2. The listing displays 
the end date of study treatment, the study day on which treatment was discontinued 
(relative to start of study treatment), and the reason for treatment discontinuation. 
5.2 Protocol deviations 
The number and percentage of subjects with at least one important protocol deviation will 
be summarized in a table by treatment group and overall on the FAS. The number and 
percentage of subjects with at least one deviation in each category and sub-category will 
also be presented. Similar tables will be produced for: 
• subjects with at least one protocol deviation, regardless of importance (i.e., important 
or non-important) 
• subjects with at least one important protocol deviation related to COVID-19 
• subjects with at least one protocol deviation related to COVID-19, regardless of 
importance (i.e., important or non-important) 
These tables will be repeated on the RND if the RND and FAS differ by more than 5%. 
Important and non-important protocol deviations will be displayed in a listing on the 
screened set. It will include all deviation descriptions, identifiers and categories. Subjects 
without any protocol deviations will not be included in this listing. 
5.3 Analysis sets 
The number and percentage of subjects included in the RND and FAS will be summarized 
in a table, by planned treatment group (i.e., as randomized) and overall, for the RND. 
A similar table will be produced for the SAF as treated. 
The inclusion/exclusion of subjects for each analysis set will be listed for the SCR. A listing 
displaying both planned and actual treatment groups will be produced for subjects having 
received in error a treatment different from the one they were randomized to. 
5.4 Subject characteristics 
5.4.1 Demographics 
Demographic characteristics will be summarized by treatment group and overall using 
descriptive statistics for continuous and categorical data on the FAS. It will include the 
following characteristics: 
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• Age (years) at hospital admission (continuous; categorized according to EudraCT as: 
adults [18–64], and elderly [65–84 and ≥ 85]) 
• Sex (categorized as: Male, Female) 
• Race (categorized as: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Other, Not permitted as 
per legislation/regulation) 
• Ethnicity (categorized as: Hispanic or Latino, Not Hispanic or Latino, Unknown, Not 
permitted as per legislation/regulation) 
• Body weight (kg) at hospital admission 
• Height (cm) 
• Body mass index (kg/m2), derived as weight (kg) / (height [cm] / 100)2 
• Geographical location, derived from the country of enrollment (categorized as: USA 
vs non-USA, Europe vs non-Europe) 
All these characteristics will be displayed in a listing. 
The variables ‘Woman of childbearing potential’ and ‘Reason for not being of childbearing 
potential’ will not be summarized but will be listed. 
This table will be repeated on the RND if the RND and FAS differ by more than 5%, and 
on the SAF if the FAS and the SAF differ by more than 5%. 
This table will also be produced for the good neurological recovery subgroup (subjects who 
had mGCS ≥ 14 and aNIHSS = 0 prior to study drug start) and its complement. 
5.4.2 Baseline disease characteristics 
5.4.2.1 Stratification factors  
The following variables will be summarized by treatment group on the FAS using 
descriptive statistics for categorical variables: 
• Age at hospital admission categorized as: ≤ 60, > 60 
• WFNS grade as assessed in the IRT system (categorized as: I–II, III–V) 
• Patient population: high-risk vs early treatment 
This table will be repeated on the RND if the RND and FAS differ by more than 5%, and 
on the SAF if the FAS and the SAF differ by more than 5%. 
This table will also be produced for the good neurological recovery subgroup (subjects who 
had mGCS ≥ 14 and aNIHSS = 0 prior to study drug start) and its complement. 
5.4.2.2 WFNS, total Glasgow Coma Scale score and motor deficit at hospital 
admission 
WFNS grade, total Glasgow Coma Scale (GCS) score and presence of motor deficit at 
hospital admission will be summarized by treatment group and overall using descriptive 
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statistics for continuous and categorical data on the FAS. This table will include the 
following characteristics: 
• WFNS grade as assessed in the IRT system (categorized as: I, II, III, IV, V) 
• GCS score (ranges from 3 [deep coma] to 15 [fully awake person], continuous and 
categorized as: 3–6, 7–12, 13–14, 15]) 
• Motor deficit (categorized as: Present, Absent) 
This table will also be repeated on the RND if the RND and FAS differ by more than 5%, 
and on the SAF if the FAS and the SAF differ by more than 5%. 
• As ‘WFNS grade at hospital admission’ is collected both in the eCRF and in the IRT 
system. If there is a confirmed discrepancy at the time of database lock between the 
eCRF and the IRT system the following table will be produced: WFNS grade as 
assessed by investigator (categorized as: I, II, III, IV, V) 
• WFNS grade as assessed by investigator (categorized as: I–II, III–V) 
It will also be repeated on the RND if the RND and FAS differ by more than 5%, and on 
the SAF if the FAS and the SAF differ by more than 5%. 
These characteristics (WFNS grade, total GCS score, and presence of motor deficit) 
evaluated at hospital admission, post aneurysm-securing procedure, and prior to 
randomization will be displayed in a listing for the FAS. 
The discrepancies between WFNS collected in eCRF and in the IRT system will be flagged 
in the listing and the value collected in the eCRF system will also be displayed.  
5.4.2.3 Neurological scales after admission and prior to Study drug initiation 
The last available modified GCS (mGCS) and abbreviated National Institutes of Health 
Stroke Scale (aNIHSS) collected prior to study drug initiation will be summarized by 
treatment group and overall using descriptive statistics for continuous variable on the FAS. 
This table will be repeated on the RND if the RND and FAS differ by more than 5%, and 
on the SAF if the FAS and the SAF differ by more than 5%. 
5.4.2.4 aSAH-related characteristics 
Current aSAH-related characteristics will be summarized by treatment group and overall, 
using descriptive statistics for continuous and categorical data on the FAS. It will include 
the following characteristics: 
• Aneurysm-securing procedure(s) performed prior to study drug initiation (categorized 
as: surgical clipping, endovascular coiling, other). If the two procedures have been 
sequentially used, only the latest one will be used 
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• Time (hours, continuous) elapsed between date/time of the aneurysm rupture and stop 
date/time of the aneurysm-securing procedure(s) when they are both available (i.e., no 
imputation for missing or partial dates and times) 
• Location of the ruptured aneurysm (Supraclinoid internal carotid artery segments, 
Middle cerebral artery segments, Anterior cerebral artery segments, Anterior 
communicating artery, Posterior communicating artery, Distal vertebral artery 
segments, Basilar artery, Posterior cerebral artery segments, Other) 
• Largest diameter of the ruptured aneurysm (mm) (continuous and categorized as: ≤ 5, 
> 5) 
• Total number of aneurysm(s) repaired (ruptured or unruptured, categorical). 
• Time from aSAH to end of the securing procedure (until the end of the last procedure 
used) 
• Number of previous aSAH episodes (categorical) 
• Total number of unruptured aneurysm(s) repaired (categorical) 
• Occurrence of complications of the aneurysm-securing procedure (categorical: yes, 
no) and by type (Intracranial hemorrhage, Intraoperative cerebral artery thrombosis, 
Cardiac arrest, Seizure, Intracranial hypertension, Brain edema or swelling, Cerebral 
infarction/ischemia, Cerebral vasospasm, Artery dissection, Severe hemodynamic 
event, Other coiling or other surgical complications). The categories are not mutually 
exclusive 
This table will be repeated on the RND if the RND and FAS differ by more than 5%, and 
on the SAF if the FAS and the SAF differ by more than 5%. 
This table will also be produced for the good neurological recovery subgroup (i.e., subjects 
who had mGCS ≥ 14 and aNIHSS = 0 prior to study drug start) and its complement. 
Subject-level current aSAH history and the peri-operative complications will be provided 
in a listing. Another listing will be produced displaying the aneurysm-securing 
procedure(s) performed prior to study drug initiation for all subjects. 
5.4.3 Other baseline characteristics 
5.4.3.1 Computed tomography scan results 
The following common findings at hospital admission as adjudicated by the Independent 
Radiology Committee (IRC) Review will be summarized by treatment group and overall 
on the FAS: 
• Hydrocephalus 
• Intraparenchymal hemorrhage 
• Intraventricular hemorrhage 
• Extracerebral hematoma 
• Ventricular drainage 
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• Intracranial pressure monitoring device 
• Midline shift 
The number and percentage of subjects with at least one finding will also be presented.  
The clot thickness will be summarized overall and separately for the good neurological 
recovery subgroup (i.e., subjects who had mGCS ≥ 14 and aNIHSS = 0 prior to study drug 
start) and its complement, according to the following categories:  
• Diffuse thick, Diffuse thin, Local thick, Local thin, None, Unable to assess. 
• Diffuse thick, Other, Unable to assess. 
All these tables will also be repeated on the RND if the RND and FAS differ by more than 
5%, and on the SAF if the FAS and the SAF differ by more than 5%. 
5.4.4 Medical history and concomitant diseases and/or diagnoses 
Reported terms are mapped to Preferred Terms (PTs) using MedDRA v25. 
Medical history covers all diseases or diagnoses ended before or on the day of ICF 
signature (i.e., ongoing question is answered “No” in the eCRF). 
Concomitant diseases and/or diagnoses are all diseases or diagnoses started before the 
day of ICF signature and ongoing at time of ICF signature (i.e., ongoing question is 
answered “Yes” in the eCRF). 
Concomitant diseases and/or diagnoses not related to a protocol mandated procedure 
are all diseases or diagnoses not related to a study protocol mandated procedure started 
between ICF signature (included) and study drug initiation.  
Medical history and concomitant diseases and/or diagnoses will be summarized separately 
on the FAS, by treatment group and overall. The number and percentage of subjects with 
at least one item of medical history are presented overall and by individual PT. Medical 
history and concomitant diseases and/or diagnoses will be sorted by descending 
frequencies of preferred name based on all treatment groups combined. This table will also 
be repeated on the RND if the RND and FAS differ by more than 5%. 
A listing will be produced for all subjects with medical history, concomitant diseases 
and/or diagnoses and concomitant diseases and/or diagnoses not related to study protocol 
mandated procedure. The concomitant diseases and/or diagnoses not related to study 
protocol mandated procedure and started between ICF signature and study drug initiation 
will be flagged. 
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5.4.5 Previous and concomitant therapies 
5.4.5.1 Previous/concomitant medications 
Therapies collected will be coded using the WHO Drug Global reference dictionary that 
employs the WHO Anatomical Therapeutic Chemical (ATC) classification system. The 
WHO Drug Global version used for reporting (B format 1 March 2022) will be specified 
in the footnote of the applicable output.  
The medications will be summarized on the FAS according to the categories displayed in 
Table 3.  
Table 3 
Definition of categories for reporting previous/concomitant 
medications 
Category 
Definition 
Previous medications  
Start and end date before the signature of the ICF  
Study concomitant medications 
Ongoing or started after ICF  
Study treatment concomitant 
medications  
Ongoing at time of Study treatment initiation 
or 
Start date equal to or after study drug initiation but before or 
the day of study drug discontinuation 
Study concomitant medications started 
during the 24 h follow-up period 
following study drug discontinuation 
Start date after study drug discontinuation and up to 24 h 
study drug discontinuation 
ICF = informed consent form. 
 
Number (%) of subjects having taken at least one previous or concomitant medication will 
be presented overall and by treatment group, by ATC class (level 4 or next highest available 
level), and preferred name within each ATC class. A table will be produced for each 
category described in Table 3. Previous and concomitant medications will be sorted by 
ATC class and preferred name within each ATC class by descending frequency based on 
all treatment groups combined. These tables will also be repeated on the RND if the RND 
and FAS differ by more than 5%. 
If the start date/time is missing, the medication will be considered as concomitant with the 
study and with the study treatment unless the end date is before the signature of the ICF or 
before study drug initiation, respectively. 
If both start and end date are missing, the medication will be considered as concomitant 
with the study and with the study treatment. 
If the start and/or end date are partially missing, the medication will be considered as 
concomitant with the study treatment and/or with the study unless it contradicts with the 
partial information available. For general rules regarding management of partial dates see 
Section 10.1. 
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A listing will be produced for all subjects with previous/concomitant medications (all 
categories specified in Table 3). This listing will include a flag identifying the medication 
started after ICF signature and before study drug initiation.  
5.4.5.2 Non-drug treatments/interventions 
Non-drug therapies, except rescue therapies, are defined as follows: 
• Intracranial pressure monitoring 
• Ventricular drainage 
• Shunt (ventriculoperitoneal or ventriculoatrial) 
• Subdural/epidural hematoma evacuation 
• Lumbar drainage 
• Mechanical ventilation 
• Tracheostomy 
• Intra-Aortic Balloon Counter-Pulsation 
The number and percentage of subjects having started at least one non-drug 
treatment/intervention will be presented (i) overall and by therapies and (ii) overall and by 
treatment group on the FAS. It will be displayed overall and by period of emergence (prior 
to randomization; from randomization [included] up to hospital discharge [included]; from 
hospital discharge up to Week 12 [included]; after Week 12). Therapies will be sorted by 
descending frequency based on all treatment groups combined. 
For general rules regarding management of partial dates see Section 10.1. 
A listing will be produced for all subjects who received a non-drug treatment/intervention. 
5.4.5.3 Rescue therapies 
Rescue therapies will be summarized on the FAS according to the categories displayed in 
Table 4. 
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Table 4 
Definition of categories for rescue therapies 
Category 
Definition 
Protocol-Specific Rescue Therapy 
• 
Non-drug treatment/intervention: balloon angioplasty 
reported as ‘cerebral angioplasty’. 
• 
Concomitant medications reported as: (i) Intravenous 
vasodilators which were preceded by intra-arterial 
vasodilators or cerebral angioplasty, or (ii) 
intra-arterial/intrathecal/intra-cisternal/intraventricular 
administration of vasodilators or ozagrel, i.e., CM ticked 
as rescue medication in the eCRF and with one of the 
following ATC codes: C08CA, C08DA, G04BE, 
C01DA, C01CE, B01AC, R03DX, A03AD and those 
started with C04. 
Local rescue therapy 
• 
Concomitant medications reported as ‘Administered as a 
rescue medication for vasospasm’, excluding Protocol-
Specific Rescue Therapy defined above. 
• 
All therapies reported as ‘Other’ on the ‘Non-drug 
treatment/intervention’ form. 
ATC = Anatomical Therapeutic Chemical. 
 
The incidence of protocol-specific rescue therapy and local rescue therapy within each 
treatment group will be displayed overall and by period of emergence together with the 
exact 95% confidence interval (CI) (Clopper-Pearson formula). The corresponding 
between-treatment group difference will be tested using a Cochran-Mantel-Haenszel 
(CMH) stratified by factors used in the randomization, i.e., WFNS grade (I–II vs III–V) 
and age (≤ 60 and > 60 years) at admission. Both will be tested at the two-sided 
significance level of alpha = 0.05. Treatment effect will be quantified by means of the 
relative risk reduction (RRR) for clazosentan together with its 95% CI. 
The use of rescue therapy overview will be produced by treatment group and overall on 
the FAS and will display: 
• Number (%) of subjects having received at least one protocol-specific rescue therapy 
• Number (%) of subjects having received at least one local rescue therapy 
• Number (%) of subjects having received at least one protocol-specific or local rescue 
therapy 
• Number (%) of subjects having received at least one protocol-specific, non-drug 
treatment / intervention (balloon angioplasty reported as ‘cerebral angioplasty’) 
• Total number of days with protocol-specific rescue therapy, excluding overlap, i.e., if 
several rescue therapies are given on the same day, then the duration under rescue 
therapy is one day 
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• Total number of days with protocol-specific rescue therapy or local rescue therapy, 
excluding overlap, i.e., if several rescue therapies are given on the same day, then the 
duration under rescue therapy is one day 
The following tables will be produced by treatment group on the FAS, by period of 
emergence (from randomization up to hospital discharge (included), and from hospital 
discharge up to Week 12 (included): 
• The number and percentage of subjects having received at least one protocol-specific 
non-drug treatment / intervention rescue therapy overall, and by ATC code 
• The number and percentage of subjects having received at least one protocol-specific 
medication rescue therapy overall, and by ATC code 
• The number and percentage of subjects having received at least one local non-drug 
treatment / intervention rescue therapy overall, and by ATC code 
• The number and percentage of subjects having received at least one local medication 
rescue therapy overall, and by ATC code 
Hospital discharge date (time) is defined as the latest end/discharge date (time) reported 
with subject location equal to ‘Critical care unit or equivalent’, ‘Specialized care ward’ or 
‘General care ward’ among the location reported for the initial hospitalization. 
For general rules regarding management of partial dates see Section 10.1. 
Rescue medications will be sorted by descending frequency of the number of subjects in 
the clazosentan group. 
Tables will also be repeated on the RND if the RND and FAS differ by more than 5%. 
Listings with all rescue medication defined in Table 4 will be produced on the FAS, 
including the category (protocol-specific vs local), the period of emergence and the number 
of days relative to study drug initiation. 
5.5 Study treatment exposure and compliance 
Study treatment duration and compliance are defined for the treatment period. 
5.5.1 Exposure 
Study treatment duration (in days) is defined as the number of days between the study 
treatment start date/time and the study treatment end date/time, regardless of treatment 
interruptions.  
The descriptive statistics on the study treatment duration will be displayed overall and by 
treatment group for the SAF, Duration in subject-years will also be summarized. The 
definition of a year is 365.25 days. 
Study treatment duration will also be summarized using the following categories ≤ 3,  
> 3–≤ 5, > 5–≤ 10, > 10–≤ 14 and > 14 days. 
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A listing will be produced displaying the study treatment duration and include the reason 
for permanent study treatment discontinuation. 
5.5.2 Compliance with study treatment 
Compliance with study treatment will be assessed using the proportion of subjects having 
received the study treatment for the expected duration as per the protocol: for a maximum 
of 14 days, for at least 10 days in the high-risk stratum, and for at least 6 days in the early 
treatment stratum. For each subject the observed treatment duration (difference between 
datetime of study drug start and stop excluding periods of temporary study drug 
interruptions) will be categorized as: 
• ‘Lower than expected’ if the observed treatment duration is < 10 days or < 6 days for 
subjects in the in the high-risk or early treatment stratum respectively. 
• ‘As expected’ if the observed treatment duration is ≥ 10 and ≤ 14 days or ≥ 6 and 
≤ 14 days for subjects in the in the high-risk or early treatment stratum respectively 
• ‘Higher than expected’ if the observed treatment duration is > 14. 
These categories will be summarized overall and by treatment group using descriptive 
statistics for categorical variable on the FAS separately for the high-risk and early treatment 
stratum. 
Number of days treated will also be summarized overall and by treatment group using a 
frequency table on the FAS for the high-risk and early treatment stratum separately. 
6 
EFFICACY VARIABLES AND ANALYSES 
A listing will be produced on the FAS with the individual data used in the analyses of the 
primary endpoint (including sensitivity analyses), the main secondary endpoint (including 
the originally planned main secondary endpoint [see Section 11.1 for details]), and the 
other secondary endpoints (i.e., poor mRS and poor GOSE).  
Tables displaying SAS procedure outputs will be produced for the main analysis of the four 
endpoints included in the hierarchical testing strategy. 
6.1 Overview 
If not otherwise stated, and according to the intent-to-treat principle, all the analyses 
presented in this section will be performed ‘as randomized’ and ‘as stratified’, that is, 
according to the treatment group and stratum allocated in the IVRS system. 
If not otherwise stated, all analyses stratified/adjusted on the randomization stratification 
factors will be stratified/adjusted on [see Section 11.2 for details]: 
• Hospital admission WFNS grade (as collected in IVRS) dichotomized as I–II vs III–V 
• Age at hospital admission ≤ 60 vs > 60 years 
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6.1.1 Overall testing strategy 
Four null hypotheses will be tested according to a hierarchical procedure, at the two-sided 
significance level of 0.05 until first non-rejection. 
The first null hypothesis H10, is that there is no difference between clazosentan 15 mg/h 
and placebo in the occurrence of clinical deterioration due to DCI from study drug initiation 
up to 14 days post-study drug initiation. The alternative hypothesis H1a is that there is a 
difference between these groups: 
H10: p1,plac = p1,clazo vs H1a: p1,plac ≠ p1,clazo 
Here p1,plac and p1,clazo denote the incidence of clinical deterioration due to DCI in the 
placebo and clazosentan groups, respectively. This hypothesis will be tested at a two-sided 
significance level of 0.05. 
Superiority will be concluded if the lower limit of the two-sided 95% CI for the RRR of 
clazosentan compared to placebo is greater than 0. 
The second null hypothesis H20, which will be tested only if H10 is rejected, is that there 
is no difference between clazosentan and placebo in the occurrence of clinically relevant 
cerebral infarction at Day 16 post-study drug initiation defined as: all-cause cerebral 
infarction ≥ 5 cm3 or cerebral infarction < 5 cm3 in subjects with clinical deterioration due 
to DCI. The alternative hypothesis H2a is that there is a difference between these groups: 
H20: p2,plac = p2,clazo vs H2a: p2,plac ≠ p2,clazo 
Here p2,plac and p2,clazo denote the incidence of occurrence of clinically relevant cerebral 
infarction at Day 16 post-study drug initiation defined as: all-cause cerebral infarction 
≥ 5 cm3 or cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI in 
the placebo and clazosentan groups, respectively. This hypothesis will be tested at a 
two-sided significance level of 0.05. 
Superiority will be concluded if the lower limit of the two-sided 95% CI for the RRR of 
clazosentan compared to placebo is greater than 0. 
The third null hypothesis H30, which will be tested only if H20 is rejected, is that there is 
no difference between clazosentan and placebo in the proportion of subjects with a poor 
mRS score at Week 12 post-aSAH. The alternative hypothesis H3a is that there is a 
difference between these groups: 
H30: p3,plac = p3,clazo vs H3a: p3,plac ≠ p3,clazo 
Here p3,plac and p3,clazo denote the proportion of subjects with a poor mRS at Week 12 
post-aSAH in the placebo and clazosentan groups, respectively. This hypothesis will be 
tested at a two-sided significance level of 0.05. 
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Superiority will be concluded if the lower limit of the two-sided 95% CI for the RRR of 
clazosentan compared to placebo is greater than 0. 
The fourth null hypothesis H40, which will be tested only if H30 is rejected, is that there is 
no difference between clazosentan and placebo in the proportion of subjects with a poor 
Glasgow Outcome Scale – Extended (GOSE) score at Week 12 post-aSAH. The alternative 
hypothesis H4a is that there is a difference between these groups: 
H40: p4,plac = p4,clazo vs H4a: p4,plac ≠ p4,clazo 
Here p4,plac and p4,clazo denote the proportion of subjects with a poor GOSE at Week 12 
post-aSAH in the placebo and clazosentan groups, respectively. This hypothesis will be 
tested at a two-sided significance level of 0.05. 
Superiority will be concluded if the lower limit of the two-sided 95% CI for the RRR of 
clazosentan compared to placebo is greater than 0. 
The study will be considered successful if the first null hypothesis (H10) is rejected. 
6.1.2 Estimands 
The estimands [ICH 2019] associated with endpoints described in Section 6.1.1 and their 
four attributes are given in Table 5. Estimands are defined by four attributes: Target 
population, Endpoint, Strategy for addressing intercurrent events (IEs), and 
Population-level summary. 
The IEs considered in this study are: 
Intercurrent Event 
Affects 
primary 
endpoint  
Affects main 
secondary 
endpoint 
Affects other 
secondary 
endpoints 
Death 
Yes 
Yes 
Yes 
Unevaluable for neurological status and 
received rescue therapy for relevant vasospasm 
Yes 
Yes 
Yes 
Unevaluable for neurological status for 
vasospasms-related-reason 
Yes 
No 
No 
Early discharge followed by rehospitalization 
due to DCI 
Yes 
No 
No 
Early discharge without follow-up at Day 14 
Yes 
No 
No 
Withdrawal of consent 
Yes 
Yes 
Yes 
Rescue therapy for non-relevant vasospasm 
Yes 
Yes 
Yes 
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DCI = delayed cerebral ischemia. 
 
IEs considered for the primary endpoint (clinical deterioration due to DCI) can be 
categorized as:  
• IE suggestive of a clinical deterioration: death, unevaluable for neurological status 
and received rescue therapy for relevant vasospasm, unevaluable for neurological 
status for vasospasms-related reason, early discharge followed by rehospitalization 
due to DCI 
• IE precluding assessment of the endpoint: withdrawal of consent and early discharge 
without follow-up at day 14 
• IE that may affect the occurrence of clinical deterioration: use of rescue therapy for 
non-relevant vasospasm 
• IE that can impact the estimation of treatment effect: permanent/temporary treatment 
discontinuation 
IEs considered for the main secondary endpoint (clinically relevant cerebral infarction) are:  
• IE suggestive of a cerebral infarction: death 
• IE precluding assessment of the endpoint: withdrawal of consent  
• IE that may affect the occurrence of clinical deterioration and thus ultimately cerebral 
infarction: use of rescue therapy (independently of whether it was provided for a 
relevant or non-relevant vasospasm) 
• IE that can impact the estimation of treatment effect: permanent/temporary treatment 
discontinuation 
IEs considered for the other secondary endpoints are the same as those for the main 
secondary endpoint. 
The strategies used in this study to address IEs are: 
• Composite strategy: The IE is incorporated into the outcome variable, e.g., any 
subject who died is assumed to meet the endpoint 
• Hypothetical strategy: When the IE occurred, the observed (or missing) values are 
substituted by the ones of a hypothetical scenario where the IE would have not 
occurred, e.g., final outcome for a subject that withdrew consent is predicted using 
the data collected up to the time of consent withdrawal 
• Treatment policy: The data collected are analyzed irrespective of the occurrence of 
the IE, e.g., the final outcome of a subject is analyzed irrespective of whether the 
subject discontinued study treatment 
Permanent/temporary treatment discontinuation 
Yes 
Yes 
Yes 
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Within a given estimand different strategies are employed depending on the type of IEs 
considered. The efficacy estimands are detailed in Table 5. The estimands’ differences vs 
the primary or secondary estimand (as appropriate) are indicated in bold.
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6.1.3 Overview of primary and secondary efficacy analyses including subgroups 
Table 6 
Overview of primary and secondary efficacy planned analyses, 
including subgroups 
Endpoint 
details 
Analysis 
Model 
Analysis 
set 
Primary efficacy endpoint: Occurrence of clinical deterioration due to DCI from study drug initiation 
up to 14 days post-study drug initiation 
 
Main analysis  
CMH test stratified by WFNS and age at 
admission  
FAS 
 
Supportive analysis (alternative 
model) 
Logistic regression adjusted for WFNS and 
age at admission 
FAS 
 
Supportive analysis (impact of 
rescue therapy) 
CMH test stratified by WFNS and age at 
admission  
FAS 
 
Supportive analysis 
(neurological deterioration 
assessed on neuroscales only) 
CMH test stratified by WFNS and age at 
admission 
FAS 
 
Subgroups 
CMH test stratified by WFNS and age.at 
admission, by subgroup 
FAS 
 
Subgroups 
Logistic regression adjusted for WFNS and 
age at admission (treatment by subgroup 
interaction) 
FAS 
Main secondary efficacy endpoint: Occurrence of clinically relevant cerebral infarction at Day 16 
post-study drug initiation. 
 
Main analysis 
CMH test stratified by WFNS and age at 
admission 
FAS 
 
Supportive analysis (alternative 
model) 
Logistic regression adjusted for WFNS and 
age at admission 
FAS 
 
Supportive analysis (initially 
planned analysis) 
CMH test stratified by WFNS and age at 
admission 
FAS 
 
Subgroups 
CMH test stratified by WFNS and age.at 
admission, by subgroup  
FAS 
 
Subgroups 
Logistic regression adjusted for WFNS and 
age at admission (subgroup as a factor)  
FAS 
Other secondary endpoint: Long-term clinical outcome assessed by the mRS at Week 12 post-aSAH 
Good vs 
poor 
Main analysis 
CMH test stratified by WFNS, age at 
admission, and good neurological recovery 
FAS 
Good vs 
poor 
Supportive analysis (alternative 
model) 
Logistic regression adjusted for WFNS, age 
at admission, and good neurological 
recovery 
FAS 
Raw 
ordinal 
score 
Supportive analysis (alternative 
model) 
Proportional odds model adjusted for 
WFNS, age at admission, and good 
neurological recovery 
FAS 
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Endpoint 
details 
Analysis 
Model 
Analysis 
set 
Good vs 
poor 
Supportive analysis (out-of-
window assessments) 
CMH with imputation of out of time window 
assessments  
FAS 
Good vs 
poor 
Subgroups 
CMH test stratified by WFNS and age at 
admission  
FAS 
Good vs 
poor 
 
Subgroups 
Logistic regression adjusted on WFNS and 
age at admission (treatment by subgroup 
interaction) 
FAS 
Other secondary endpoint: Long-term clinical outcome assessed by the GOSE at Week 12 post-aSAH 
Good vs 
poor 
Main analysis 
CMH test stratified by WFNS, age at 
admission, and good neurological recovery 
FAS 
Good vs 
poor 
Supportive analysis (alternative 
model) 
Logistic regression adjusted for WFNS, age 
at admission, and good neurological 
recovery 
FAS 
Raw 
ordinal 
score 
Supportive analysis (alternative 
model) 
Proportional odds model adjusted for 
WFNS, age at admission, and good 
neurological recovery 
FAS 
Good vs 
poor 
Supportive analysis (out-of-
window assessments) 
CMH with imputation of out of time window 
assessments  
FAS 
Good vs 
poor 
Subgroups 
CMH test stratified by WFNS and age at 
admission  
FAS 
Good vs 
poor 
Subgroups 
Logistic regression adjusted on WFNS and 
age at admission (treatment by subgroup 
interaction) 
FAS 
aNIHSS = abbreviated National Institutes of Health Stroke Scale; aSAH = aneurysmal subarachnoid hemorrhage, CMH 
= Cochran-Mantel-Haenszel; CT = computed tomography; DCI = delayed cerebral ischemia; FAS = Full analysis 
set; GOSE = Glasgow Outcome Scale – Extended; mGCS = modified Glasgow Coma Scale; mRS = modified 
Rankin Scale; WFNS = World Federation of Neurological Societies. 
 
6.2 Primary endpoint  
6.2.1 Variable  
The primary endpoint is the occurrence of clinical deterioration due to DCI from study 
drug initiation up to 14 days post-study drug initiation. 
The Clinical Event Committee (CEC) will indicate for each subject the absence/presence 
of clinical deterioration due to DCI according to the rules specified in the CEC charter.  
During the primary review, the CEC member may answer ‘Unknown’ if and only if there 
is a lack of data overall or if poor imaging quality does not allow the assessment on the 
presence of clinical deterioration or the causality of clinical deterioration to be made with 
sufficient certainty.  
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In that case, the primary CEC reviewers will discuss the case and try to come to an 
agreement during the consensus meeting. If an agreement cannot be reached during the 
consensus meeting, an adjudication meeting will take place. 
The final assessment cannot be ‘Unknown’. 
6.2.2 Intercurrent events for the main estimand 
IEs include death, unevaluable for neurological status and received rescue therapy for 
relevant vasospasm, unevaluable for neurological status for vasospasms-related reason, 
and early discharge followed by rehospitalization due to DCI. As these events may reflect 
the occurrence of a clinical deterioration due to DCI, they will be addressed using a 
composite strategy, i.e., they will all lead the CEC to conclude (as per CEC charter) that 
the subject met the primary efficacy endpoint. 
The withdrawal of consent and the early discharge without follow-up at day 14 are two IEs 
precluding further assessment of the neurological status of the subjects. However, they are 
not systematically associated with the occurrence of clinical deterioration. For instance, 
subjects in good clinical condition might be discharged early from the intensive care unit 
(ICU) to free up space for more severe subjects. These IEs will thus be addressed using a 
hypothetical strategy. The CEC will make a medical judgment based on the totality of the 
data available up to the time of the occurrence of the IE to determine what would have been 
the outcome of the subject if neuroscales had been collected up until Day 14. 
Use of rescue therapy for a non-relevant vasospasm is part of standard-of-care / current 
practices. So far, the real efficacy of these rescue therapies has not been demonstrated. 
They will thus be addressed using a treatment policy strategy. 
Permanent/temporary treatment discontinuation will be addressed using a treatment policy 
strategy. 
6.2.3 Handling of missing data 
Subjects randomized and treated 
The CEC will provide a final assessment (yes or no) on the primary endpoint, indicating 
for each subject whether it has been met, therefore it is assumed that there will not be any 
missing data for the primary endpoint.  
There will be no missing data for the stratification variables included in the analysis since 
these variables are used as stratification factors for the randomization. 
Subjects randomized but not treated 
No further data will be collected for these subjects. They will not be reviewed by the CEC 
and will be considered as having met the primary endpoint, i.e., the worst possible outcome 
is assumed. 
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6.2.4 Hypothesis, statistical model and assumptions 
The null hypothesis (H0) is that the occurrence of clinical deterioration due to DCI in 
subjects treated with clazosentan is not different from placebo. The alternative hypothesis 
(HA) is that the event rate in the clazosentan group differs from the placebo group. 
6.2.5 Main analysis 
The main analysis for the primary endpoint will be performed on the FAS, according to the 
intent-to-treat approach. 
The observed incidence rates will be displayed together with the exact 95% confidence 
intervals (CIs) (Clopper-Pearson).  
For the main estimand, the null hypothesis will be tested using a CMH test stratified by 
factors used in the randomization, i.e., WFNS grade (I–II vs III–V) and age (≤ 60 and > 60 
years) at admission, at the two-sided significance level of alpha = 0.05. 
The treatment effect (clazosentan vs placebo) will be expressed in terms of RRR with 
corresponding 95% CIs. An RRR greater than 0 will indicate a response to treatment in 
favor of clazosentan over placebo.  
Homogeneity of the treatment effect across strata will be investigated using the 
Breslow-Day test. Should there be any indication that the odds ratios (ORs) are not 
homogeneous, emphasis will be given to the within-strata OR rather than the common OR 
for the interpretation of the treatment effect.  
The treatment effect will be described, each with its 95% CL, with:  
• The absolute difference in the rates 
• The OR 
• The RRR 
6.2.6 Supportive analyses 
6.2.6.1 Logistic regression 
As a supplementary estimand, a logistic regression model will be used instead of the CMH 
test on the FAS. 
The primary endpoint is expected to follow a binomial distribution. Accordingly, the 
treatment effect of clazosentan relative to the placebo will be assessed using a logistic 
regression adjusted for stratification factors, i.e., hospital admission WFNS grade (I–II vs 
III–V), and age at hospital admission (≤ 60 and > 60 years). 
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The generalized linear model used for estimating the treatment effect is: 
log (p/(1-p)) = α + β1 × WFNS + β2 × age + β3 × treatment 
where: 
• p refers to the probability of the event (i.e., the probability of meeting the endpoint) 
• treatment refers to clazosentan and placebo (reference is placebo) 
• WFNS refers to hospital admission WFNS grade dichotomized as I–II vs III–V  
• age refers to that at hospital admission dichotomized as ≤ 60 and > 60 years. 
The coefficients α, β1, β2, and β3 will be estimated by the method of maximum likelihood.  
Treatment effect will be summarized by the OR, the corresponding 95% Wald CI and the 
p-value derived from the Wald statistic (Type III analysis of effects). Least Squares means 
for adjusted event rate (probability scale) by treatment group with corresponding 95% CIs 
will also be computed.  
6.2.6.2 Rescue therapy for non-relevant vasospasms 
A supplementary estimand will evaluate the robustness of the primary analysis with regards 
to the rescue therapies (i.e., any rescue therapy as defined in Section 5.4.5.3) that may have 
been given for non-relevant vasospasms. In the main analysis, this IE is addressed using a 
treatment policy because the efficacy of these medications has not been demonstrated. To 
assess the robustness of the primary efficacy analysis with regards to rescue therapy given 
for non-relevant vasospasms, the primary analysis will be repeated but addresses this IE 
using a composite strategy, i.e., all subjects having received a rescue therapy between study 
drug initiation and Day 14 will be considered as meeting the primary endpoint. 
6.2.6.3 Deterioration due to DCI (based on neuroscales only) and death 
A supplementary estimand will evaluate the robustness of the primary analysis with regards 
to the substitution rules defined in the CEC charter to accommodate the situation where a 
subject was not evaluable and, consequently, the neuroscales were not assessed. The 
primary analysis will be repeated but considers an alternative definition of the primary 
endpoint that can only be met following: (i) the occurrence of death or (ii) a clinical 
deterioration due to DCI based on neuroscales only. Hence, all subjects alive at Day 14 and 
meeting the primary endpoint according to CEC but without evidence of clinical 
deterioration based on the neuroscale measurements (i.e., patients having a “Yes” for 
question 1 “Has the primary endpoint been met?” and a “No” for question 2 “Did the patient 
have at least one episode of clinical deterioration due to DCI?” of the CEC eCRF) will be 
considered in this analysis as not meeting the primary endpoint. 
6.2.7 Subgroup analyses 
The aim of these exploratory subgroup analyses, classifying subjects according to 
important baseline characteristics, is to explore the consistency of treatment effect in a 
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variety of relevant subject subgroups to support the efficacy evaluation of clazosentan in 
this indication. 
The following pre-specified subgroups may be considered for the analyses:  
• WFNS grade at hospital admission dichotomized as I–II vs III–V 
• Age (years) at hospital admission dichotomized as ≤ 60 vs > 60 
• Geographical location (USA vs non-USA ; Europe vs non-Europe) 
• Race (White; Black or African American; Asian).  
• Sex (Female vs Male) 
• Type of aneurysm-securing procedure (coiling vs clipping). If both were used, the last 
one is used for analysis. 
• Good neurological recovery (Y/N): subjects who had mGCS ≥ 14 and aNIHSS = 0 
prior to study drug start. 
• Full neurological recovery (Y/N): subjects who had mGCS = 15 and aNIHSS = 0 
prior to study drug start. 
Results of the subgroup analyses will be displayed in a table as well as in a forest plot 
including: 
• An estimate of the treatment effect (OR for clazosentan vs placebo) with its 95% CI 
for each level of each subgroup. It will be calculated using the CMH estimator of the 
common OR obtained separately in each subgroup level (i.e., including the subgroup 
and its complementary) as described for the main analysis. When a subgroup is 
defined by a stratification variable the corresponding stratification variable will be 
excluded from the analysis. 
• A vertical reference line displayed at the level of the overall treatment effect.  
The subgroup analyses will also be performed using a logistic regression model stratified 
by hospital admission WFNS grade (I–II vs III–V), and age at hospital admission 
(≤ 60 and > 60 years) and including terms for ‘subgroup’, ‘treatment’ and ‘treatment by 
subgroup’ interaction. Results will be summarized in a table and will include: 
• An estimate of the treatment effect (OR for clazosentan vs placebo) with its 95% CI 
for each level of each subgroup (i.e., including the subgroup and its complementary)  
• A p-value for the interaction tests  
Additional subgroup analyses for the primary endpoint may also be conducted for factors 
that are identified with a statistically significant treatment × factor interaction. 
The study is not designed or powered to detect interactions, but an arbitrary two-sided 
significance level of alpha = 0.10 will be used for the interpretation of the interaction test. 
No multiplicity adjustment is introduced as the subgroup analyses are exploratory in nature. 
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If there are issues due to very small sample sizes (e.g., interaction test failing due to 
presence of observed zero cells), the use of other methods may be considered. 
6.2.8 Other analyses 
If the FAS and the RND populations differ by more than 5%, then the main analysis will 
be repeated on the RND. 
The initially planned analysis of the primary endpoint (up to protocol version 6 dated 
29 April 2021) will be performed as an exploratory analysis. It will consist of repeating the 
primary analysis defined in Section 6.2.5 but stratified by all the factors used in the 
randomization, i.e., WFNS grade, age at admission, and patient population (high-risk 
prevention vs early treatment) at the two-sided significance level of alpha = 0.05. 
Number of episodes of clinical deterioration due to DCI from study drug initiation and up 
to 14 days post-study drug initiation as adjudicated by the CEC will be summarized with 
descriptive statistics for categorical variables (from 1 up to the highest number of episodes 
observed) by treatment group on the FAS. 
If subjects were treated accidently, at least partially, during the study with a treatment 
different from the one they were randomized to, the main analysis will be repeated using 
the actual treatment group instead of the planned treatment group, i.e., the main analysis 
will be repeated on the SAF. 
One listing will be produced displaying both scores (mGCS and aNIHSS), the date and 
time of the assessment, and the day relative to study drug initiation.  
One listing will present the date and time of each cerebral angiogram and cerebral 
computed tomography (CT) scan performed over the course of the study. 
Selected information from data collected on the ‘Episode of clinical deterioration’ eCRF 
page, in the IRC Review eCRF and IRC Adjudication eCRF will be displayed in listings. 
Selected information from data collected in the CEC eCRF will also be displayed in 
listings. 
6.3 Main secondary endpoint  
6.3.1 Variable  
The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at 
Day 16 post-study drug initiation as defined by the two following components: 
• Component 1: all-cause cerebral infarction ≥ 5 cm3. This will be evaluated (yes/no) 
for all subjects by IRC and will be confirmed by the CEC 
• Component 2: for all subjects with a “no” at component 1, then the presence of 
cerebral infarction < 5 cm3 (as assessed by IRC) will be evaluated in subjects with 
clinical deterioration due to DCI (as assessed by the CEC) 
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Cerebral infarction refers to new or worsened infarcts and is determined by central 
radiology review comparing the total volume of infarcts on the CT scan performed 16 days 
after study drug initiation with the total volume on the CT scan performed post-procedure. 
If the CT scan cannot be performed on Day 16, then it is acceptable for the CT to be 
performed within the 7 days following Day 16. If a subject is discharged from the hospital 
prior to Day 16, the CT scan is performed on the day of hospital discharge. Clinical 
deterioration due to DCI and cerebral infarctions ≥ 5 cm3 are confirmed by the CEC. 
Cerebral infarctions < 5 cm3 in subjects with clinical deterioration due to DCI are derived 
from both the CEC data (primary endpoint) and IRC data (for infarct size). 
6.3.2 Intercurrent events for the main estimand 
Similar to that stated for the primary endpoint regarding death and DCI, the occurrence of 
death prior to Day 16 may be related to cerebral infarction. Consequently, the occurrence 
of death will be addressed using a composite strategy, i.e., all subjects who died will be 
considered as meeting the main secondary endpoint. 
The withdrawal of consent before Day 16 is an IE precluding the carrying out of the Day 
16 CT scan. The first component of the endpoint withdrawal of consent will be addressed 
using a hypothetical strategy where the CEC will make a medical judgment based on the 
totality of the data available up to the time of consent withdrawal to determine what would 
have been the outcome of the subject if the Day 16 CT scan would have been available. 
For all subjects who (i) withdrew consent, (ii) met the primary endpoint, and (iii) do not 
meet the first component of the main secondary endpoint, then the second component of 
the main secondary endpoint cannot be derived if the Day 16 CT scan is missing. These 
subjects will thus be considered as meeting the main secondary endpoint (according to 
imputation rule for missing data defined in Section 6.3.3). 
Use of rescue therapy as defined in this study are part of standard-of-care / current 
practices. So far, the real efficacy of these therapies/medications has not been 
demonstrated. Therefore, they will be addressed using a treatment policy strategy. 
Permanent/temporary treatment discontinuation will be addressed using a treatment policy 
strategy. 
6.3.3 Handling of missing data 
Subjects randomized and treated 
The CEC will provide a final assessment (yes/no) on the first component of the main 
secondary endpoint, indicating for each subject whether it has been met. Therefore, it is 
assumed that there will not be any missing data for this component. However, patients not 
meeting the first component of the endpoint may have a missing Day 16 CT scan (no CT 
scan performed 14 days after study drug start or later) preventing the assessment of the 
second component of the endpoint. If the second component of the endpoint cannot be 
derived, then the subjects meeting the primary endpoint will be considered as meeting the 
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main secondary endpoint, i.e., the worst possible outcome is assumed. As per protocol, if 
a subject is discharged before Day 16 but not earlier than Day 14, the “Day 16 CT scan” 
can be done on the day of discharge. It follows that “Day 16 CT scan” will be considered 
missing for the evaluation of the second component of the endpoint when there is no CT 
scan performed 14 days after study drug start or later. 
There will be no missing data for the variables included in the model since these variables 
are collected as stratification factors for the randomization. 
Subjects randomized and not treated 
No further data will be collected for these subjects. They will not be reviewed by the CEC 
and will be considered to have met the primary endpoint [see Section 6.2.3] and the main 
secondary endpoint, i.e., the worst possible outcome is assumed.  
6.3.4 Hypothesis, statistical model and assumptions 
The null hypothesis (H0) is that the occurrence of clinically relevant cerebral infarction at 
Day 16 post-study drug initiation in subjects treated with clazosentan is not different from 
placebo. The alternative hypothesis (HA) is that the event rate in the clazosentan group 
differs from the placebo group. 
6.3.5 Main analysis 
The proportion of subjects with occurrence of clinically relevant cerebral infarction at 
Day 16 post-study drug initiation will be analyzed in a similar manner as the primary 
efficacy endpoint [see Section 6.2.5 for details]. 
The main statistical analysis for the main secondary endpoint will be performed on the FAS 
according to the intent-to-treat approach. 
The null hypothesis will be tested using a CMH test stratified by factors used in the 
randomization, i.e., WFNS grade and age at admission, at the two-sided significance level 
of alpha = 0.05. 
6.3.6 Supportive analyses 
Logistic regression 
As a supplementary estimand, a logistic regression model will be used on the FAS instead 
of the CMH test following the same approach as the one considered for the supportive 
analysis of the primary endpoint described in Section 6.2.6.1. 
6.3.7 Subgroup analyses 
Exploratory subgroup analyses may be conducted using the same approach and on the same 
subgroups as the ones defined for the primary endpoint analysis described in Section 6.2.7. 
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The study is not designed or powered to detect interactions, but an arbitrary two-sided 
significance level of alpha = 0.10 will be used to interpret the interaction test. No 
multiplicity adjustment is introduced as the subgroup analyses are exploratory in nature. 
If there are issues due to very small sample sizes (e.g., interaction test failing due to 
presence of observed zero cells), the use of other methods may be considered.  
6.3.8 Other analyses 
If the FAS and the RND populations differ by more than 5%, then the main analysis will 
be repeated on the RND. 
The initially planned primary analysis of the main secondary endpoint (up to protocol 
version 6 dated 29 April 2021) will be performed as an exploratory analysis. It will consist 
of repeating the primary analysis defined in Section 6.3.5 on the first component only of 
the endpoint as defined in Section 6.3.1. For this analysis the CMH will be stratified by all 
the factors used in the randomization, i.e., WFNS grade at hospital admission (I–II vs III–
V), age (≤ 60 and > 60 years) at hospital admission, and patient population (high-risk 
prevention vs early treatment) at the two-sided significance level of alpha = 0.05. 
If subjects were treated accidently, at least partially, during the study with a treatment 
different from the one they were randomized to, the main analysis will be repeated using 
the actual treatment group instead of the planned treatment group, i.e., the main analysis 
will be repeated on the SAF. 
Listings will be produced on the RND displaying all the data collected in the IRC Review 
eCRF (e.g., common findings, clot size, vasospasm severity, reviewer’s comment, total 
infarct volume on post-procedure CT scan, total infarct volume on Day 16 CT scan, volume 
of new and worsened infarcts on Day 16 CT scan). 
6.4 Other secondary endpoint 
The other secondary endpoint is long-term clinical outcome assessed by the mRS and the 
GOSE at Week 12 post-aSAH. The structured interview for the GOSE allows for 
simultaneous derivation of the mRS.  
6.4.1 Modified Rankin Scale 
6.4.1.1 Variable  
The raw mRS scores range from 0 (no symptoms) to 6 (dead) and will be dichotomized for 
analysis into poor (a score of 3 to 6) vs good (a score of 0 to 2) outcome. 
6.4.1.2 Intercurrent events for the main estimand 
Deaths are included in the mRS. Therefore, the occurrence of death will be addressed using 
a composite strategy where all subjects that died prior to Week12 (i.e., died prior to day 
84 + 21 days post-aSAH) will have a mRS score of 6 irrespective of whether a prior 
assessment was available. 
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The withdrawal of consent before the collection of the mRS assessment (Week 12) will be 
addressed using a hypothetical scenario. The final outcome for the subject will be derived 
based on the mGCS data collected up to the time of consent withdrawal as per the 
imputation rule for missing data defined in Section 6.4.1.3. 
Use of rescue therapy as defined in this study are part of standard-of-care / current 
practices. So far, the real efficacy of these therapies/medications has not been 
demonstrated. Therefore, they will be addressed using a treatment policy strategy. 
Permanent/temporary treatment discontinuation and out-of-window assessments will be 
addressed using a treatment policy strategy. 
6.4.1.3 Handling of missing data 
Subjects randomized and treated 
If the mRS score from the Week 12 interview is missing, and the subject did not die prior 
to Week 12 (i.e., did not die prior to day 84 + 21 days post-aSAH), the missing mRS score 
is replaced by the score 4 (moderately severe disability) with the following exception: 
• If the patient had their mGCS score reported at least once per day, from the study 
drug initiation up to 14 days post-study drug initiation (or up to the time of discharge 
if subject is discharged before Day 14 but after having completed study treatment as 
per protocol), and all reported scores, regardless of day and time point, are ≥ 14 and 
the location where the subject was discharged after the initial hospitalization at the 
investigational study center is home, then the missing mRS is substituted with 2 
(slight disability). 
Subjects randomized but not treated 
If the subject is still alive at the time they withdraw from study, a missing mRS score will 
be replaced by the score 4 (moderately severe disability). 
6.4.1.4 Hypothesis, statistical model and assumptions 
The null hypothesis (H0) is that the proportion of subjects with poor clinical outcomes 
treated with clazosentan is not different from the placebo group. The alternative hypothesis 
(HA) is that the event rate in the clazosentan group differs from the placebo group. 
6.4.1.5 Main analysis 
The proportion of subjects for each possible score value will be summarized in a table and 
in a figure by treatment group on the FAS. 
The proportion of subjects with poor (a score of 3 to 6) clinical outcomes (mRS) at 
Week 12 post-aSAH will be analyzed in a similar manner as the primary efficacy endpoint 
[see Section 6.2.5 for details] but adding the good neurological recovery (mGCS ≥ 14 and 
aNIHSS = 0, Yes/No) variable as an adjustment variable. 
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All available assessments (including out-of-window ones) will be used in the analysis. 
6.4.1.6 Supportive/sensitivity analyses 
6.4.1.6.1 Out-of-window assessments 
The main analysis will be repeated but replacing the assessments outside of the 84 ± 21days 
post-aSAH time window by imputed ones according to the imputation rule for missing data 
defined in Section 6.4.1.3. 
6.4.1.6.2 Logistic regression 
This analysis relies on a logistic regression model on the FAS instead of the CMH test. The 
same approach as the one considered for the supportive analysis of the primary endpoint 
described in Section 6.2.6.1 will be used but adding the good neurological recovery (mGCS 
≥ 14 and aNIHSS = 0, Yes/No) variable as an adjustment variable. 
6.4.1.6.3 Proportional odds regression model 
A proportional odds model (POM) adjusted on WFNS grade (I–II vs III–V), age 
(≤ 60 and > 60 years) at admission and good neurological recovery (mGCS ≥ 14 and 
aNIHSS = 0, Yes/No) will be used as a supportive analysis to assess treatment effect on 
raw mRS data (i.e., on ordinal score) on the FAS. Results of the POM will be presented by 
the OR, the corresponding 95% Wald CL, and the p-value derived from the Wald statistic 
(type III analysis of effects). The validity of the proportional odds assumption will be 
assessed by fitting a fully non-proportional odds model. Departure from the proportional 
odds assumption will be evaluated on the forest plot displaying the departure of all 
individual slopes (and associated p-values) compared to the reference slope for each effect. 
If the proportional odds assumption is not satisfied for some variables, then partially 
proportional odds models could be considered to estimate and test treatment effect. 
6.4.1.7 Subgroup analyses 
The main analysis will be repeated on the following pre-defined subgroups (and 
corresponding complementary subgroups) but without adjusting for good neurological 
recovery: 
• Good neurological recovery: subjects who had mGCS ≥ 14 and aNIHSS = 0 prior to 
study drug start. 
• Full neurological recovery: subjects who had mGCS = 15 and aNIHSS = 0 prior to 
study drug start.  
Additional exploratory subgroup analyses may also be conducted with the same approach 
as the one defined for the primary endpoint in Section 6.2.7. 
6.4.1.8 Other analyses 
If the FAS and the RAND populations differ by more than 5%, then the main analysis will 
be repeated on the RND analysis set. 
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Listings  
One listing will be produced displaying both scores (GOSE and mRS), the date and time 
of the assessment, the number of days elapsed since aSAH, and the respondent’s identity 
(subject and/or proxy and/or legal representative). 
Figures 
For the GOSE and mRS, the distribution of subjects for each level will be provided in a 
graphical format. 
6.4.2 Glasgow Outcome Scale – Extended  
6.4.2.1 Variable  
The raw GOSE scores range from 1 (dead) to 8 (upper good recovery) and will be 
dichotomized for analysis into poor outcome (score ≤ 4) and good outcome (score > 4).  
6.4.2.2 Intercurrent events for the main estimand 
Death is included in the GOSE. Therefore, occurrence of death will be addressed using a 
composite strategy where all subjects that died prior to Week 12 (i.e., died prior to day 
84 + 21 days post-aSAH) will have a GOSE score of 1 irrespective of whether a prior 
assessment was available.  
The withdrawal of consent before the collection of the GOSE assessment (Week 12) will 
be addressed using a hypothetical scenario. The final outcome for the subject will be 
derived based on the mGCS data collected up to the time of consent withdrawal as per the 
imputation rule for missing data defined in Section 6.4.2.3. 
Use of rescue therapy as they are defined in this study are part of standard-of-care / current 
practices. So far, the real efficacy of these therapies/medications has not been 
demonstrated. Therefore, they will be addressed using a treatment policy strategy. 
Permanent/temporary treatment discontinuation will be addressed using a treatment policy 
strategy. 
6.4.2.3 Handling of missing data 
Subjects randomized and treated 
If the GOSE score from the Week 12 interview is missing, and the subject did not die prior 
to Week 12 (i.e., did not die prior to day 84 + 21 days post-aSAH), the missing GOSE 
score is replaced by the score 3 (lower severe disability), with the following exception: 
• If the subject had their mGCS score reported at least once per day, from study drug 
initiation up to 14 days post-study drug initiation (or up to the time of discharge if 
subject is discharged before Day 14 but after having completed study treatment as per 
protocol), and all reported scores regardless of day and time point are ≥ 14, and the 
location where the subject was discharged after the initial hospitalization at the 
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investigational study center is home, then the missing GOSE is substituted with 5 
(lower moderate disability). 
Subjects randomized but not treated 
If the subject is still alive at the time they withdraw from study, a missing GOSE score will 
be replaced by the score 3 (lower severe disability). 
6.4.2.4 Hypothesis, statistical model and assumptions 
The null hypothesis (H0) is that the proportion of subjects with poor clinical outcome 
treated with clazosentan is not different from placebo. The alternative hypothesis (HA) is 
that the event rate in the clazosentan group differs from the placebo group. 
6.4.2.5 Main analysis 
The proportion of subjects for each possible score value will be summarized in a table and 
in a figure by treatment group on the FAS. 
The proportion of subjects with poor (a score of 1 to 4) clinical outcome (GOSE) at 
Week 12 post-aSAH will be analyzed in a similar manner as for the primary efficacy 
endpoint [see Section 6.2.5 for details] but adding the good neurological recovery 
(mGCS ≥ 14 and aNIHSS = 0, Yes/No) variable as an adjustment variable. 
All available assessments (including those performed out-of-window) will be used in the 
analysis. 
6.4.2.6 Supportive/sensitivity analyses 
6.4.2.6.1 Out-of-window assessments 
The main analysis will be repeated but replacing the assessments outside of the 84 ± 21days 
post-aSAH time window by imputed ones according to the imputation rule for missing data 
defined in Section 6.4.2.3. 
6.4.2.6.2 Logistic regression 
This analysis relies on a logistic regression model on the FAS instead of the CMH test. The 
same approach as the one considered for the supportive analysis of the primary endpoint 
described in Section 6.2.6.1 will be used but adding the good neurological recovery (mGCS 
≥ 14 and aNIHSS = 0, Yes/No) variable as an adjustment variable. 
6.4.2.6.3 Proportional odds regression model 
A POM adjusted on WFNS grade (I–II vs III–V), age (≤ 60 and > 60 years) at admission 
and good neurological recovery (mGCS ≥ 14 and aNIHSS = 0, Yes/No) will be used as a 
supportive analysis to assess treatment effect on raw GOSE data (i.e., on ordinal score) on 
the FAS. Results of the POM will be presented by the OR, the corresponding 95% Wald 
CL, and the p-value derived from the Wald statistic (type III analysis of effects). The 
validity of the proportional odds assumption will be assessed by fitting a fully non-
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proportional odds model. Departure from the proportional odds assumption will be 
evaluated on the forest plot displaying the departure of all individual slopes (and associated 
p-values) compared to the reference slope for each effect. If the proportional odds 
assumption is not satisfied for some variables, then partially proportional odds models 
would be considered to estimate and test treatment effect. 
6.4.2.7 Subgroup analyses 
The main analysis will be repeated on the following pre-defined subgroups (and their 
corresponding complementary) but without adjusting for good neurological recovery: 
• Good neurological recovery: subjects who had mGCS ≥ 14 and aNIHSS = 0 prior to 
study drug start. 
• Full neurological recovery: subjects who had mGCS = 15 and aNIHSS = 0 prior to 
study drug start.  
Additional exploratory subgroup analyses may also be conducted with the same approach 
as the one defined for the primary endpoint on subgroups including but not limited to the 
ones defined in Section 6.2.7. 
6.4.2.8 Other analyses 
If the FAS and the RND populations differ by more than 5%, then the main analysis will 
be repeated on the RND. 
Listings  
One listing will be produced displaying both scores (GOSE and mRS), the date and time 
of the assessment, the number of days elapsed since aSAH, and the respondent’s identity 
(subject and/or proxy and/or legal representative).  
Figures 
For the GOSE and mRS, the distribution of subjects for each level will be provided in a 
graphical format: one bar per treatment group and per variable, where each bar shows 100% 
of the discrete value. 
6.5 Subject-reported endpoints  
The analysis of the effect of clazosentan on long-term clinical outcome, cognition, and 
health-related QoL at Week 12 post-aSAH will be described together as described in this 
section. 
To evaluate the effect of clazosentan on cognition, the following endpoints will be used: 
• Cognitive status, as assessed by the change from baseline to Day 14 post-study drug 
initiation on the Montreal Cognitive Assessment (MoCA), for those subjects that have 
a score at both time points 
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• Cognitive status, as assessed by the change from baseline to Week 12 post-aSAH on 
the MoCA, for those subjects that have a score at both time points 
• Cognitive status, as assessed by the change from Day 14 post-study drug initiation to 
Week 12 post-aSAH on the MoCA, for those subjects that have a score at both time 
points 
• Cognitive status as assessed by the MoCA at Day 14 post-study drug initiation and at 
Week 12 post-aSAH 
To evaluate the effect of clazosentan on health-related QoL post-aSAH, the following 
endpoints will be used:  
• Generic QoL as measured by the EQ-5D-5L at Week 12 and Week 24 post-aSAH 
• Oxford Participation and Activities Questionnaire (Ox-PAQ) at Week 12 post-aSAH 
• Disease-specific QoL as measured by the Stroke-Specific Quality of Life (SS-QoL) at 
Week 12 post-aSAH 
6.5.1 Montreal Cognitive Assessment 
6.5.1.1 Variables 
The MoCA will be used to detect cognitive impairment. The variables that will be analyzed 
are: 
• The value at each assessment for the domain scores and the total score. 
• The change from baseline to each post-treatment visit (i.e., Day 14 post-study drug 
initiation and Week 12) for the domains scores and the total score. 
• The change from Day 14 post-study drug initiation to Week 12 for the domains scores 
and the total score. 
If the assessment for one domain is missing, the total score is not computed. All 
assessments performed after Day 14 will be analyzed as Week 12 assessments. 
6.5.1.2 Analysis 
The tables, figures and listings will be produced on the FAS. 
Tables 
Descriptive statistics for both domain scores and the total score will be computed by 
treatment group on the FAS for: 
• change from baseline to each visit and the corresponding actual values at each visit 
• change from Day 14 post-study drug initiation to Week 12 post-aSAH and the 
corresponding actual values at Day 14 post-study drug initiation and at Week 12 post-
aSAH 
• actual values at each visit (including subjects having missing values at any visit) 
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A table with descriptive statistics (number and percentage of subjects) on the reason for 
not performing the test will also be produced.  
Treatment effect in MoCA total score will be assessed using a mixed model for repeated 
measures for the actual values at each post-baseline visit (i.e., Day 14 post-study drug 
initiation and Week 12) using an unstructured variance/covariance matrix and the 
following covariates: WFNS grade (I–II vs III–V) at admission, age (≤ 60 and > 60 years) 
at admission, visit (as a factor), treatment group, and visit by treatment interaction. Least 
Squares means and 95% CI will be computed for each treatment group and visit and for 
the between-group difference at each visit.  
In addition, changes from baseline to post-baseline visits will be analyzed using the same 
mixed model but with an additional covariate for baseline MoCA total score. Treatment 
effect in MoCA total score will also be assessed using an analysis of variance (ANOVA) 
fitted on change from Day 14 post-study drug initiation to Week 12 and including the 
following covariates: WFNS grade (I–II vs III–V) at admission, age (≤ 60 and > 60 years) 
at admission, Day 14 MoCA total score, and treatment group. This treatment effect 
estimate could have been derived from the mixed model for repeated measures on the 
change from baseline to post-baseline visits defined above but because of the missing 
baseline values this analysis should provide a more precise estimate of the change from 
Day 14 to Week 12. 
Additional analyses may also be conducted using the same approaches on pre-defined 
subsets such as: 
• Good neurological recovery: subjects who had mGCS ≥ 14 and aNIHSS = 0 prior to 
study drug start. 
• Full neurological recovery: subjects who had mGCS = 15 and aNIHSS = 0 prior to 
study drug start. 
Figures 
The evolution of the total score over time will be provided in a graphical format from 
baseline to Week 12 (one boxplot per treatment group and analysis visit).  
Listings 
A listing will provide date and time of assessment, the reason for not performing the 
MoCA, the total score at each visit, the absolute change from baseline to each post-baseline 
visit in total score and the change from Day 14 post-study drug initiation to Week 12 post-
aSAH in total score. The values taken into account for the analysis will be flagged. It will 
also include the day relative to study drug initiation and the number of days elapsed since 
aSAH. 
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6.5.2 EQ-5D-5L 
6.5.2.1 Variables 
The EQ-5D (5L version) questionnaire will be used at Week 12 and Week 24 post-aSAH 
to assess the subject’s QoL. The variables that will be analyzed are: 
• To characterize an EQ-5D health state: The responses of the 5 dimensions combined 
ranging from 
 (full health) to 
 (worst health) 
• To characterize the health utility: The EQ-5D health state converted into a single 
summary index value and continuous value ranging from 0 to 1 (value less than 0 
represent health states regarded as worse than death) using a crosswalk link function. 
Following the latest guidance of the NICE published in 2022, the value set provided 
by Hernández Alava et al. [Hernández-Alava 2017] for the UK will be used to derive 
the health utility score  
• To characterize the overall self-rated health status: The value of the visual analog 
scale (VAS) score, ranging from 0 (worst imaginable health) to 100 (best imaginable 
health) 
All assessments performed before Day 126 (midpoint between Week 12 and Week 24) 
will be analyzed as Week 12 assessments and all those performed after will be analyzed 
as Week 24 assessments. If a subject has two assessments allocated to the same week 
then only the last assessment will be used for analysis. 
6.5.2.2 Analysis 
The tables, figures and listing will be produced on the FAS. 
Tables 
The health state and corresponding respondent (e.g., subject, proxy) will be summarized 
by visit and treatment group, using descriptive statistics for categorical and continuous 
data. The health utility and VAS will be summarized by visit and treatment group, using 
descriptive statistics for continuous data.  
Change from Week 12 to Week 24 in health utility and VAS will be summarized by 
treatment group, using descriptive statistics for continuous data.  
For the health state, between-group comparison domain by domain will be performed using 
a POM (unadjusted). It will provide the OR and corresponding 95% CI (normal 
approximation) for each domain. 
For the overall health status (VAS score) and the health utility, between-group comparisons 
at Week 12 and Week 24 will be performed using ANOVAs with factors for WFNS grade 
(I–II vs III–V) at admission, age (≤ 60 and > 60 years) at admission, and treatment group. 
Least Squares means and 95% CLs will be computed for each treatment group and for the 
difference between clazosentan and placebo groups. Between-group comparison of the 
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In the second part of the questionnaire, a bar plot will be produced by variable and 
treatment group displaying the proportions of subjects for each category. 
Listings 
A listing will be produced to display all computed scores. A second listing will provide the 
answers to the second part of the questionnaire and related reported scores. It will also 
include the number of days elapsed since aSAH.  
6.6 Multivariate long-term outcome 
6.6.1 Variables 
The long-term clinical outcome of the patients will be evaluated by jointly analyzing the 
following variables: 
• GOSE total score at Week 12 
• mRS total score at Week 12 
• EQ-5D utility value at Week 12 
• EQ-5D utility value at Week 24 
• Ox-PAQ raw domain scores at Week 12 
• SS-QoL total score at Week 12 
• MoCA at Week 12 
• Change from baseline to Week 12 in MoCA 
6.6.2 Analysis 
All Week 12 assessments will be analyzed jointly using a normed Principal Component 
Analysis (PCA). This analysis will be done in R [R Core Team 2020] using the function 
“dudi.pca” of the R-package ‘ade4” [Chessel 2004]. As the PCA requires complete cases, 
subjects with at least one missing value will be excluded from the analysis. The treatment 
effect will be characterized using a between-class analysis [Dolédec 1987] and tested using 
a permutation test [Romesburg 1985] at the two-sided significance level of alpha = 0.05 on 
the between-groups inertia (i.e., multi-dimensional between-treatment group variance) 
percentage. This analysis will be repeated but imputing missing assessment with the 
observed overall mean of the corresponding variable. The analysis might also be repeated 
excluding the variables with the highest frequencies of missing values and/or including 
change from baseline to Week 12 in MoCA and Week 24 assessment of EQ-5D. 
The following outputs will be produced: 
• Distribution of the eigen values of the PCA  
• Contribution of the variables to the principal components of the PCA  
• Factorial maps of the PCA 
• Factorial maps of the between-class analysis 
• Permutation test on the between-group inertia percentage 
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6.7 Analysis of pharmaco-economic variables 
The tables, figures and listings will be produced on the FAS. 
• Number and type of episodes of rescue therapy, from randomization up to hospital 
discharge and from hospital discharge up to Week 12 [see Section 5.4.5.3] 
• Number and type of specific (pre-specified) medical treatments and therapies from 
randomization up to hospital discharge and from hospital discharge up to Week 12 
[see Section 5.4.5.2] 
• Length (in days) of initial and total ICU stay, length (in days) of total hospitalization, 
and duration (in days) in different hospital care units, from randomization up to 
hospital discharge and from hospital discharge until Week 12 
• Intensity of rehabilitation care up to Week 12 post-aSAH 
• First post-hospital discharge location 
• Duration (in days) of home care support post-initial hospital discharge 
• Employment status at Week 24 (6 months) post-aSAH 
6.7.1 Rescue therapies 
See Section 5.4.5.3 for details. 
6.7.2 Specific (pre-specified) medical treatments and therapies 
See Section 5.4.5.2 for details. 
6.7.3 Subject location/rehabilitation 
6.7.3.1 Variables 
For each subject, the following variables will be derived:  
• Length of initial ICU stay, defined as the time (days) elapsed between date of 
start/admission and date of end/discharge when location is recorded as ‘Critical care 
unit or equivalent’ (earliest record) 
• Length of total ICU stay, defined as the sum of the lengths (days) of each stay 
recorded as ‘Critical care unit or equivalent’ 
• Length of total hospitalization (in days), defined as the sum of the lengths of each 
stay recorded as ‘Critical care unit or equivalent’ or ‘Specialized care ward’ or 
‘General care ward’ 
• Length of stay in ‘Specialized care ward’ defined as the total time (days) elapsed 
between date of start/admission and date of end/discharge for each location recorded 
as ‘Specialized care ward’ 
• Length of stay in ‘General care ward’ defined as the total time (days) elapsed between 
date of start/admission and date of end/discharge for each location recorded as 
‘General care ward’ 
• Intensity of rehabilitation care up to Week 12 post-aSAH, defined as the cumulative 
number of hours in each category (none, light, moderate, intense) 
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• Post-hospital discharge location, defined as the first location the subject is admitted to 
other than ‘Critical care unit or equivalent’ or ‘Specialized care ward’ or ‘General 
care ward’ 
• Duration (days) of home care support post-hospital discharge, defined as the sum of 
the lengths of each stay in ‘Inpatient rehabilitation facility’ and ‘Assisted living 
facility’ or ‘Home partially independent’ 
Other locations recorded as a free text will not be taken into account for the computation 
of any of these durations. 
Duration in hours (for the intensity of rehabilitation care) will be derived by multiplying 
the duration of the rehabilitation in weeks by the mid class of rehabilitation intensity: 3.5, 
10.5, 17.5 hours per week. 
To compute duration in the event of a missing end date, when the question ‘Ongoing at end 
of study’ was ticked in the eCRF then the missing end date should be imputed with EOS 
date.  
6.7.3.2 Analysis 
Descriptive statistics will be provided for each of the aforementioned variables by 
treatment group.  
A first listing will present the inpatient and outpatient locations (e.g., critical care unit or 
equivalent, specialized care ward, nursing facility) with corresponding date (time) of 
start/admission and date (time) of end/discharge as well as the various lengths of stay.  
A second listing will present the intensity of the rehabilitation course and the corresponding 
start and end date as well as the corresponding duration.  
6.7.4 Employment status 
6.7.4.1 Assessments 
At Week 24 post-aSAH, the pre-aSAH employment/student status, the current 
employment/student status, and the date of return to work (or to an educational institution, 
for students, as applicable) will be collected via telephone or postal questionnaire and 
captured in the clinical database. 
The employment status is collected as follows:  
• Employed full time 
• Employed part time 
• Student full time 
• Student part time 
• On work disability 
• Homemaker 
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• Retired 
• Not employed 
• Unknown 
For both time points (pre-aSAH and Week 24 post-aSAH), the subject may select multiple 
possibilities.  
6.7.4.2 Variables 
The following variables will be derived: 
• The employment status at the given time point (including the reported combinations 
(e.g., Student part time/ Employed part time) 
• The time (days) from aSAH to return to work, the time (days) from aSAH to return to 
education 
• The change from pre- to post-aSAH status (fully back to pre-aSAH, partially back to 
pre-aSAH, not back to pre-aSAH) defined as the worst observed transition (see 
transition matrix in Appendix 14.3) between pre-aSAH and post-aSAH status. 
6.7.4.3 Analysis 
Tables and listings will be produced on the FAS. 
A table will provide the number and percentage of subjects in each category (and reported 
combinations) by treatment group for each time point. 
A table will provide the number and percentage of subjects in each category of change 
from pre- to post-aSAH status (fully back, partially back, not back) by treatment group 
with 95% Clopper-Pearson CI. 
Employment status will also be described on the FAS using descriptive statistics for the 
following variables: 
• Time from aSAH to return to work  
• Time from aSAH to return to education 
• Proportion of subjects fully back to pre-aSAH status, partially back to pre-aSAH 
status, not back to pre-aSAH 
A listing will provide the status for each time point. It will also display the date of return 
to work (or to an educational institution, for students, as applicable) and the corresponding 
number of days elapsed since aSAH. 
6.8 Biomarker endpoints analysis 
The biomarker endpoints are: 
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• Presence of abnormal S100b protein concentration defined as the max observed 
concentration between study drug start and day14 in S100b being greater than or 
equal to 0.4 µg/L 
6.8.1 Variables 
The presence of abnormal concentration of S100b between study drug start and Day 14 
will be derived. 
6.8.2 Analysis 
Tables 
Descriptive statistics for the level of S100b protein at baseline will be tabulated by 
treatment group on the FAS. The table will also display the percentages of subjects with 
S100b protein greater or equal to 0.4 μg/L at any time between study drug start and Day 14 
with corresponding 95% Clopper-Pearson CI. 
Figures 
Values over time will be provided in graphical format (boxplots) by treatment group.  
Listings 
One listing will be provided for the FAS. It will include all results from the central 
laboratory. The maximum concentration observed that will be used to derive the endpoint 
will be flagged. It will also include the day relative to study drug initiation.  
7 
SAFETY VARIABLES AND ANALYSES 
If not otherwise stated: 
• All tables and listings will be produced on the SAF 
• Subjects will be evaluated according to the actual treatment they received, which may 
differ from the randomly assigned treatment 
In the event of an administration error, i.e., a subject was administered both placebo and 
active treatment, the subject will be analyzed as active treatment (‘clazosentan’).  
For partial date handling see Section 10.1. 
7.1 Adverse events 
The original terms used by the investigators to describe adverse events (AEs) in the 
Adverse Events eCRF are assigned a PT and a System Organ Class (SOC) for classification 
and tabulation using MedDRA v25. 
Subjects who experienced the same AE more than once (as qualified by the same PT) are 
counted only once. 
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7.1.1 Variables 
All adverse events 
All AEs are those occurring from signature of the ICF until EOS visit, which are believed 
to be related to a protocol-mandated procedure as well as treatment-emergent adverse 
events (TEAEs).  
Treatment-emergent adverse events  
An AE is treatment-emergent if the onset date/time ≥ start date/time of study treatment up 
to 24 hours after study treatment discontinuation. 
An incomplete (time, day or month missing) or missing AE date will be imputed as 
described in the Table 7. The ‘lower limit’ and ‘upper limit’ refer to the earliest and latest 
possible date/times, respectively. As an example: If AE onset date is MAR2017 (time and 
day missing), the lower limit is 01MAR2017 T00:00:01 and the upper limit is 31MAR2017 
T23:59:59; if AE onset date is 2017 (time, day and month missing), the lower limit is 
01JAN2017T00:00:01 and the upper limit is 31DEC2017T23:59:59. 
Table 7 
Imputation rules for an incomplete or missing AE datetime 
Field 
Incomplete datetime 
Missing datetime 
AE resolution 
datetime 
The upper limit. 
No imputation: the AE is 
considered as ongoing. 
AE onset 
datetime 
The rules below apply in the order presented: 
1. If the (imputed) AE end datetime is on or after the 
start of study treatment, and if the study treatment 
start falls within the upper and lower limits 
(inclusive), the study treatment start datetime is used. 
2. If the AE resolution datetime is missing, and: 
if the study treatment start falls within the upper and 
lower limits (inclusive), the study treatment start 
datetime is used. 
3. In all the other cases, the lower limit is used. 
Whichever is the earlier of the 
AE resolution datetime or 
study treatment start datetime. 
AE = adverse event. 
 
If the emergence of an AE cannot be determined based on the above imputation rules, the 
AE will be considered as treatment-emergent.  
The purpose of imputing AE dates is only to determine the treatment emergence of an AE 
for the summary tables and listings. However, only the actual dates as reported in the eCRF 
will be listed. No imputed date is considered in the medical evaluation of an AE. 
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Treatment-emergent adverse events related to study treatment  
An AE is considered related to the study treatment if the investigator answered “related” 
to the question “Relationship to study treatment”. If the relationship is missing, the AE is 
considered ‘related’. 
Treatment-emergent adverse events by intensity 
The intensity of an AE is determined by the investigator as ‘mild’, ‘moderate’ or ‘severe’.  
Subjects who experienced the same AE more than once (as qualified by the same PT), but 
with different intensities, are counted only once, using the worst reported intensity. If the 
intensity is missing, the event is considered severe. 
Serious adverse events 
An AE is considered serious if the investigator answered, “Yes” on the question 
“Serious?”.  
Serious treatment-emergent adverse events 
Serious AEs (SAEs) are considered treatment-emergent if their onset date/time ≥ start 
date/time of study treatment up to 24 hours after study treatment discontinuation. 
Serious adverse events during the long-term follow-up 
SAEs with an onset date/time ≥ end date/time of study drug + 24 hours and up to EOS. 
Adverse events leading to death 
An AE is considered fatal if the investigator ticked “Fatal” on the question “Outcome”. 
Adverse events leading to premature discontinuation of study treatment  
An AE is considered leading to premature discontinuation of study treatment if the 
investigator ticked “Permanently discontinued” on the question “Action taken with study 
treatment”. 
Adverse events of special interest 
An AE is considered an AE of special interest (AESI) if it is treatment-emergent and 
belongs to any of the categories listed below (the corresponding MedDRA PTs/SMQs 
using MedDRA v25 are provided in Appendix 14.4):  
• Brain oedema 
• Cerebral haemorrhage 
• Anaemia 
• Lung complications 
• Hypotension 
• Oedema and fluid retention 
• Tachyarrhythmia 
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• Hepatic disorders  
Rescue therapy-specific adverse events 
An AE is considered related to the rescue therapy if the investigator answered “related” to 
the question “Relationship to rescue therapy” in the AE page. 
7.1.2 Analysis 
An overview of the AEs by treatment group will be produced on the SAF. It will include 
the N (%) of subjects having at least one treatment-emergent: 
• AE 
• AE related to study treatment 
• AE of severe intensity 
• SAE 
• SAE related to study treatment 
• AE of special interest 
• AE with a fatal outcome 
• AE with a fatal outcome and related to study treatment  
• AE leading to temporary interruption of study treatment 
• AE leading to permanent discontinuation of study treatment 
It will also include the N (%) of subjects having at least one: 
• SAE during the long-term follow-up 
• SAE during the long-term follow-up with fatal outcome 
The tables specified in Table 8 will summarize the number (%) of subjects by treatment 
group based on the SAF. 
Table 8 
Summary of adverse event analyses  
Category 
Approach 
All AEs 
 
All TEAEs  
- N (%) of subjects having at least one event by SOC and PT (overall 
and by patient population high-risk prevention vs early treatment) 
- N (%) of subjects having at least one event by PT 
- N (%) of subjects having at least one event by SOC and PT and 
maximum intensity 
TEAEs of severe intensity 
- N (%) of subjects having at least one event by SOC and PT 
TEAEs related to study treatment 
- N (%) of subjects having at least one event by and PT 
TEAEs leading to temporary 
interruption of study treatment 
- N (%) of subjects having at least one event by SOC and PT 
- N (%) of subjects having at least one event by PT 
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Category 
Approach 
TEAEs leading to permanent 
discontinuation to study treatment  
- N (%) of subjects having at least one event by SOC and PT 
- N (%) of subjects having at least one event by PT 
TEAEs with fatal outcome  
- N (%) of subjects having at least one event by SOC and PT 
- N (%) of subjects having at least one event by PT 
TEAEs with fatal outcome and 
related to study treatment  
- N (%) of subjects having at least one event by SOC and PT 
- N (%) of subjects having at least one event by PT 
Serious TEAEs 
- N (%) of subjects having at least one event by SOC and PT (overall 
and by patient population high-risk prevention vs early treatment) 
- N (%) of subjects having at least one event by PT 
SAEs during long-term follow-up 
- N (%) of subjects having at least one event by SOC and PT 
- N (%) of subjects having at least one event by PT 
Serious TEAEs related to study 
treatment 
- N (%) of subjects having at least one event by SOC and PT 
- N (%) of subjects having at least one event by PT 
SAEs with fatal outcome during 
long-term follow-up 
- N (%) of subjects having at least one event by SOC and PT 
- N (%) of subjects having at least one event by PT 
TEAEs of special interest 
- N (%) of subjects having at least one event by category of interest 
and PT 
Rescue therapy-specific AEs 
- N (%) of subjects having at least one event by PT 
AE = adverse event; PT = preferred term; SAE = serious adverse event; SOC = system organ class; TEAE = treatment-
emergent adverse event. 
 
A table will display the most frequent TEAE (at least 5% in placebo or active group) by 
treatment group and by PT. The PTs will be sorted by decreasing frequency in the active 
group. 
A table will display the primary cause of death for all deaths up to EOS by treatment group 
and by PT. The PTs will be sorted by decreasing frequency in the active group. 
For disclosure to public database purposes the following table will also be produced: 
• Treatment-emergent SAEs (including occurrences) 
• Treatment-emergent SAEs related to study treatment (including occurrences) 
• Most frequent (threshold to be defined at time of reporting) non-serious TEAEs 
(including occurrences) 
For tables presented by SOC and PT, SOCs/PTs are sorted by descending frequency of the 
number of subjects in the clazosentan group. If the frequencies of SOCs or PTs are the 
same, alphabetical order is used.  
For tables presented by PT, PTs are sorted by descending frequency of the number of 
subjects in the clazosentan group. If the frequencies of PTs are the same, alphabetical order 
is used.  
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All AEs captured from signature of ICF up to EOS will be reported in the subject listings, 
which include data collected in the eCRF as well as the coded terms (SOC, PT), a flag for 
treatment-emergent and a flag for waived event as defined in protocol section 9.1.3 
[D-22.069].  
The following additional listings will be produced: 
• All deaths and associated primary cause of death will be listed 
• All AEs of subjects randomized but not treated (RND) 
• All the previous/concomitant medications for subjects with a waived SAE. 
• All medical histories for subjects with a waived SAE. 
7.2 Laboratory tests 
Laboratory analyses are based on data received from the central laboratory. Laboratory 
data will be converted into Standard International (SI) units. Unless noted otherwise, 
summaries and listings will include scheduled, re-test, and unscheduled assessments.  
Consistent with the AE emergence period, the study treatment period considered for the 
laboratory measurements analyses is defined as start date/time of study treatment up to 
24 hours after study treatment discontinuation. 
Descriptive summary statistics on the observed values and the change from baseline to last 
value (re-test and unscheduled assessments included) in the study treatment period for 
hematology and blood chemistry parameters will be summarized.  
Marked laboratory abnormalities are defined in Table 9 in Appendix 14.5. 
Treatment-emergent marked laboratory abnormalities (MLAs) are those which are not 
present at baseline (e.g., change from no marked abnormality to any marked abnormality) 
or if a worsening occurred from study drug initiation up to 24 hours after study drug 
discontinuation, as compared to the corresponding value at baseline (e.g., change from a 
pre-existing abnormality at baseline to a worse category of abnormality). 
The number (%) of subjects with newly occurring or worsening MLAs during study 
treatment period will be tabulated. A subject will be counted only once but may be reported 
in more than one MLA criterion of a given parameter. Percentages will be based on the 
number of subjects at risk, i.e., those having at least one post-baseline value and not 
meeting the criteria at baseline (or having a missing baseline value) for a given parameter. 
Treatment-emergent liver function abnormalities occurring at any time post-baseline are 
identified according to the following criteria; a subject is considered to have met the criteria 
if they have at least one abnormality based on the worst post-baseline value measured: 
• ALT > 3, > 5, > 8 × ULN, > 10 × ULN  
• AST > 3, > 5, > 8 × ULN, > 10 × ULN 
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• AST or ALT > 3, > 5, > 8 × ULN, > 10 × ULN 
• TBL > 2 × ULN 
• TBL > 2 × ULN combined with ALT or AST > 3 × ULN 
• ALT or AST > 3 × ULN + TBL ≥ 2 × ULN + ALP < 2 × ULN 
For criteria combining several parameters, the abnormality must be reported at the same 
visit (same sample date).  
The number (%) of subjects meeting the criteria defined above will be tabulated by 
treatment group. Percentages will be based on the number of subjects at risk, i.e., those 
having at least one post-baseline value and not meeting the criteria at baseline  for a given 
parameter. In the event a subject’s baseline value is missing: 
• the subject will be considered ‘at risk’ for an abnormality formulated as a 
post-baseline value, but: 
• the subject will be considered not ‘at risk’ for an abnormality formulated as a change 
from baseline. 
A similar table will be produced on all post-baseline marked abnormalities. 
Individual results will be listed by category (e.g., Hematology, Blood chemistry), by 
subject number and by visit / study day for all subjects, including central laboratory results.  
All laboratory data for subjects with at least one MLA during study treatment will be listed. 
Any local laboratory data collected will be listed separately. 
7.3 Electrocardiography 
Descriptive summary statistics on the observed values and the change from baseline to last 
value (re-test and unscheduled assessments included) in the study treatment period for the 
12 lead ECG parameters will be summarized by treatment group on the SAF.  
The QT corrected with Fridericia’s formula (QTcF) will be derived from the reported QT 
and RR using the following formula: 
QTcF (msec) = QT (msec)/ RR1/3 
For this parameter, additional flags will be defined: 
Marked ECG abnormalities are defined below for QTcF:  
• Value > 450, Value > 480, Value > 500 
• Increase from baseline > 30, Increase from baseline > 60  
• Value > 450 and increase from baseline > 30 
• Value > 450 and increase from baseline > 60 
• Value > 500 and increase from baseline > 30 
• Value > 500 and increase from baseline > 60. 
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Number (%) of subjects with a marked QTcF abnormality during the study treatment period 
will be tabulated by treatment group. Percentages will be based on the number of subjects 
at risk, i.e., those having  at least one post-baseline value and not meeting the criteria at 
baseline for a given parameter. In the event a subject’s baseline value is missing: 
• the subject will be considered ‘at risk’ for an abnormality formulated as a 
post-baseline value, but: 
• the subject will be considered not ‘at risk’ for an abnormality formulated as a change 
from baseline. 
All data (values and changes) will be listed by assessment. The listing will include date 
and time of measurements as well as the day, relative to study drug initiation.  
7.4 Vital signs 
Descriptive summary statistics on the average daily values and the change from baseline 
to each daily average post-baseline value in the study treatment period will be summarized 
for the following parameters:  
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Heart rate (beats/min) 
• Central venous pressure (mmHg) 
• Intracranial pressure (mmHg) 
• Body temperature (°C) 
All data (values and changes) will be listed by assessment. The listing will include date 
and time of measurements as well as the day, relative to study drug initiation.  
7.5 Other safety variables and analyses 
7.5.1 Fluid balance 
Daily fluid balance will be computed by subtracting the daily input and the daily output 
when they are both available and will be categorized according to the following classes:  
Imbalance categories 
1  
2 
3 
4 
5 
6 
 7 
Class boundaries (L)  
>0,≤1 
> 1,≤2  
>2,≤3 
>3,≤4 
>4, ≤5 
>5, ≤6 
>6 
 
Negative fluid balance will not be categorized. For each subject the periods of at least two 
consecutive days with fluid balance of category 2 or higher will be flagged.  
A table displaying the proportion of subjects with at least one episode of fluid balance of 
category 2 or higher lasting for at least two consecutive days by treatment group will be 
produced on the SAF. A listing displaying daily fluid balance for all subjects will be 
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produced on the SAF. Periods of at least two consecutive days with fluid balance of 
category 2 or higher will be flagged. 
7.6 Subgroup analysis of safety variables  
The following subgroups will be used for safety analyses: 
• WFNS grade at hospital admission, dichotomized as I–II vs III–V 
• Age (years) at hospital admission, dichotomized as < 60 and ≥ 60 
• Geographical location (USA vs non-USA, Europe vs non-Europe) 
• Race (White; Black or African American; Asian). Subjects in the “Other” category 
will be excluded from the analysis given the small number of subjects. 
• Sex 
• Type of aneurysm-securing procedure (coiling vs clipping). If both were used, the last 
one is used for analysis. 
• Good neurological recovery (mGCS ≥ 14 and aNIHSS = 0 vs. complement) 
The following tables [see Table 8 for details] will be repeated on the subgroups (and their 
complements) defined above: 
• TEAEs 
• TEAEs of special interest 
• TEAEs leading to premature discontinuation of study treatment 
• Serious TEAEs 
8 
GENERAL STATISTICAL METHODOLOGY 
Descriptive statistics will be provided by treatment group depending on the nature of the 
variable:  
• For continuous variables: number of observed values, mean, standard deviation, 
minimum, first quartile, median, third quartile and maximum 
• For dichotomous or categorical variables: number of observed values, and frequency 
with percentage per level/ category 
Data are listed and summarized as described below. 
The tables will use the following header structure (label and order): 
Clazosentan 15 mg/h 
N = xxx 
Placebo 
N = xxx 
 
Where N indicates the total number randomized or treated appropriate to the analysis set 
in the corresponding treatment group, unless otherwise specified.  
9 
INTERIM ANALYSES AND DATA MONITORING COMMITTEES 
Not applicable, IDMC analyses are described in a separate SAP. 
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10 GENERAL DEFINITIONS AND DERIVATIONS 
10.1 Handling of missing date 
This section describes some general principles to be followed in the case of missing or 
incomplete dates. 
Missing dates will not necessarily be replaced (e.g., medical history). Unless specified 
otherwise, partially known dates will be defined as: 
• Partially known start date: 
– If only the day is missing, and month and year of the episode = month and year of 
study drug initiation, then  
Start date = date of study drug initiation,  
otherwise 
 
 
Start date = yyyy-mm-01. 
– If month and day are missing, and year of the episode = year of study drug 
initiation, then  
 
Start date = date of study drug initiation,  
otherwise  
 
 
Start date = yyyy-01-01 
• Partially known end date: 
– If only the day is missing, and month and year of the episode = month and year of 
study drug discontinuation, then End date = date of study drug discontinuation, 
otherwise   
 
 
End date = yyyy-mm-28 or 29 or 30 or 31 
– If month and day are missing, and year of the episode = year of study drug 
discontinuation, then if start date is less than or equal to study drug discontinuation  
then  
 
 
 
End date = date of study drug discontinuation, 
otherwise  
 
 
End date = yyyy-12-31 
The original dates without estimation will be presented in the listings. 
Any missing EOS date will be substituted with the date of database lock.  
10.2 General analysis variables 
Baseline value is defined as the last non-missing value before study drug initiation based 
on date and time (when collected). 
Analysis value is defined as the value at the visit (numeric result in standard units). 
Absolute change from baseline is defined as post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline. 
Percent change from baseline is defined as the absolute change from baseline divided by 
the baseline value (if the baseline value is > 0) and then multiplied by 100. 
Ratio to baseline is defined as the value at the visit divided by the value at baseline (if the 
baseline value is ≠ 0). 
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Analysis date is defined as the numeric SAS date derived from the date/time of assessment. 
It may be an imputed date. 
Analysis start date is defined as the numeric SAS date derived from the start date/time of 
an event. It may be an imputed date. 
Analysis end date is defined as the numeric SAS date derived from the end date/time of 
an event. It may be an imputed date. 
Analysis relative day is estimated for several assessments (e.g., vital signs, laboratory 
data). It refers to the number of days elapsed since study drug initiation date plus 1 (e.g., 
Day 1 is the day of study drug initiation). For dates prior to study drug initiation, study day 
is the negative number of days elapsed between the date under consideration and the day 
of study drug initiation. Therefore, the study day is never 0. 
Analysis day relative to aSAH is estimated for several assessments performed during 
screening period and at EOS visit (e.g., MoCA, EQ-5D-5L). It refers to the number of days 
elapsed since aneurysm rupture (aSAH) date plus 1 (e.g., Day 1 is the day of aSAH).  
Analysis end relative day is estimated for several assessments, including AE end, 
treatment interruptions, concomitant medication end. It refers to the number of days 
between the end of the specific event and the study drug initiation.  
Hospital discharge date (time) is defined as the latest end/discharge date (time) reported 
with subject location equal to ‘Critical care unit or equivalent’, ‘Specialized care ward’ or 
‘General care ward’ among the location reported for the initial hospitalization.  
Discharge home is defined as being discharged home fully or partially independent. 
Day 14 is defined as per protocol as 14th day after study drug start. This corresponds to the 
analysis relative day 15. 
10.3 Study treatment administration error 
In the event of an administration error, i.e., a subject was administered both placebo and 
active treatment, the subject will be analyzed as active treatment (‘clazosentan’) in all 
analyses based on the SAF (i.e., in all analyses based on the actual treatment group). 
10.4 Other derivations 
Length/Duration: Lengths and durations based on dates will be computed as end date 
minus start date plus 1. 
Good and Full neurological recovery subgroup variable: If one of these subgroups 
cannot be derived for a given subject due to missing data then the subject will be considered 
to be in the corresponding complementary subgroup. 
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11 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
11.1 Changes in the conduct of the study / data collection 
Addition of the EQ-5D questionnaire at Week 24 post-aSAH: 
In order to have at least one QoL assessment performed later than 12 weeks after aSAH 
subjects will be interviewed for the EQ-5D questionnaire at a second timepoint, Week 24 
post-aSAH (from protocol version 4 dated 7 January 2020). Accordingly, the study 
duration was adjusted from 3 to 6 months for the collection of the employment status, the 
EQ-5D and SAE data collection. 
Early treatment stratum: 
Following decision of the IDMC held on 2 April 2021, the recruitment into the early 
treatment stratum was stopped. This decision was based on a low rate of recruitment into 
this cohort since the outset of the study, making the contribution of these subjects to the 
overall study futile.  
Main secondary endpoint definition: 
In protocol version 7 the main secondary endpoint definition was updated: in addition to 
the already existing all-cause infarcts ≥ 5 cm3 at Day 16 post-study drug initiation, 
clinically relevant infarcts < 5 cm3 have been added. The latter are defined as those new or 
worsened infarcts < 5 cm3 that occur in subjects with CEC-adjudicated clinical 
deterioration due to DCI [see Section 6.3.1 for details]. The initially planned analysis (up 
to and including protocol version 6) will still be performed but as an exploratory analysis 
[see Section 6.3.8 for details]. 
Other secondary endpoint and testing strategy: 
Since protocol version 7 the mRS has been formally included in the statistical hierarchical 
testing strategy, just before the GOSE [see Section 6.1.1 for details]. 
11.2 Changes to the analyses planned in the study protocol 
Early treatment stratum: 
The number of subjects randomized in this stratum being very low, and according to IDMC 
decision considering the contribution of these subjects to the overall study futile, this 
stratum was no longer considered as an adjustment/stratification variable in all the analyses 
adjusted/stratified on the stratification factors used for randomization. The initially planned 
analysis of the primary endpoint (i.e., stratified on the 3 stratification factors) will be done, 
but as an exploratory analysis [see Section 6.2.8 for details]. 
Estimands: 
As the study started before the ICH E9 (R1) guidance became effective [ICH 2019], the 
estimands were not described in the protocol or in the CSR SAP version 1. They are now 
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defined in Section 6.1.2. Redefining the analyses with the estimand framework led to no 
longer using a Per-protocol analysis set and to rather defining the list of the IEs, and the 
different strategies considered to address them. 
Biomarker endpoints analysis: 
In the protocol, the biomarker endpoints are the area under the plasma concentration-time 
curve of S100b protein from baseline to Day 10 and from baseline to Day 14 post-study 
drug initiation. To accommodate the heterogeneity of the timing of the assessment, because 
some subjects may have been discharged early, and to align with previous studies, the 
following endpoint definition will be used: presence of abnormal S100b protein 
concentration defined as the max observed concentration between study drug start and 
Day 14 being greater or equal to 0.4µg/L. 
GOSE/mRS: 
In the protocol, the main analysis of the dichotomized GOSE and mRS was specified as a 
CMH test stratified on the variables used in the randomization (i.e., WFNS grade [I–II vs 
III–V] and age [≤ 60 and > 60 years] at admission). However, in previous studies it was 
found that subjects who had recovered well from their initial bleeding episode and 
aneurysm-securing procedure had on average a better GOSE/mRS score. This subgroup of 
subjects called “good neurological recovery” is defined as subjects with an mGCS ≥ 14 
and an aNIHSS = 0 (absence of motor deficit) within 60 minutes prior to study drug 
initiation. The complement subgroup is called “neurological impairment”. To gain further 
precision in treatment effect estimates, the analyses of GOSE and mRS will, in addition, 
be adjusted for good neurological recovery variable (mGCS ≥ 14 and aNIHSS = 0, 
Yes/No). 
11.3 Clarifications concerning endpoint definitions and related variables or 
statistical methods 
In protocol version 7 dated 18 February 2022, the main secondary endpoint definition was 
updated: in addition to the already existing all-cause infarcts ≥ 5 cm3 at Day 16 post-study 
drug initiation, clinically relevant infarcts < 5 cm3 have been added. The latter are defined 
as those new or worsened infarcts < 5 cm3 that occur in subjects with CEC-adjudicated 
clinical deterioration due to DCI [see Section 6.3.1 for details]. 
The protocol defines that the treatment effect for the main efficacy analyses will be 
summarized using: the absolute difference in the rates, the OR, the RR and the RRR. 
However, to avoid redundancy as RRR = 1 – RR the RR will not be presented in statistical 
outputs. 
The protocol defines the following pharmaco-economic endpoint: Number and type of 
episodes of rescue therapy, from randomization up to hospital discharge and from hospital 
discharge up to Week 12 post-aSAH. Total duration in days, rather than the number of 
episodes of rescue therapy, will be analyzed, and more specifically: (i) the total number of 
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days with protocol-specific rescue therapy and (ii) the total number of days with protocol-
specific rescue therapy or local rescue therapy [see Section 5.4.5.3 for details]. 
11.4 Additional analyses to those planned in the study protocol 
Not applicable. 
12 LIST OF TABLES, LISTINGS AND FIGURES 
The complete list of Tables, Listings and Figures is stored in the Idorsia Electronic 
Document Management System. 
For the mock-up catalog to be used during programming, please refer to the document 
stored in the Biometry Computing Environment.  
Since all Tables, Listings and Figures are produced using SAS®, the output actually 
generated may slightly differ from the mock-ups presented in the study specific mock-up 
catalog. 
13 REFERENCES 
[D-22.069] 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). 
Idorsia 
Pharmaceuticals Ltd; Protocol Version 7 ID-054-304, 18 February 2022. 
[Chessel 2004] Chessel D, Dufour A, Thioulouse J. The ade4 Package - I: One-Table 
Methods. 
R 
News. 
2004;4(1):5-10 
Available 
from: 
https://cran.r-
project.org/doc/Rnews/Rnews_2004-1.pdf 
[Dolédec 1987], Dolédec S, Chessel, D. Rythmes saisonniers et composantes stationnelles 
en milieu aquatique I- Description d’un plan d’observations complet par projection 
de variables. Acta Oecologica, Oecologia Generalis, 8, 3, 403–426. French. 
[Hernández-Alava 2017] Hernández-Alava M, Pudney, S. Econometric modelling of 
multiple self-reports of health states: the switch from EQ-5D-3L to EQ-5D-5L in 
evaluating drug therapies for rheumatoid arthritis. J Health Econ. 2017;55:139-152. 
[ICH 2019] ICH Harmonised Tripartite Guideline. Addendum on estimands and sensitivity 
analysis in clinical trials to the guideline on statistical principles for clinical trials – 
E9 (R1). 20 November 2019 [accessed on 25 July 2022]. Available from: 
https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf 
[R Core Team 2020] R-project.org [Internet]. R: A language and environment for statistical 
computing. R Foundation for Statistical Computing, Vienna, Austria. 2020 [cited 25 
July 2022]. Available from: https://www.R-project.org/ 
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[Romesburg 1985] 
Romesburg 
HC. 
Exploring, 
confirming and randomization 
tests. Computers & Geosciences. 1985;11(1):19–37. 
[Williams 1999] Williams LS, Weinberger M, Harris LE, Clark DO, Biller J. Development 
of a stroke-specific quality of life scale. Stroke. 1999 Jul;30(7):1362-9.
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14 APPENDICES 
14.1 Revision History 
Version Date 
Version 
Implemented Change(s) 
31-OCT-2018 
1.0 
Initial version 
26-JUL-2022 
2.0 
• Definition of Estimands added 
• Incorporate changes in protocol: 
– New/revised exploratory endpoints were added 
(protocol version 3) 
– EQ-5D questionnaire was added at Week 24 
post-aSAH, EOS visit was moved from 
Week 12 to Week 24, SAEs collected until 
Week 24 (protocol version 4) 
– Follow-up visit / phone call was added for 
subject discharged prior to Day 14 to allow 
assessment of primary endpoint (protocol 
version 5) 
– Discontinuation of the recruitment into the early 
treatment group following a recommendation 
received by the study IDMC on 2 April 2021 
(protocol version 6) 
– Revised definition of main secondary endpoint, 
mRS explicitly added to the overall testing 
strategy (protocol version 7) 
• Imputation rules for missing CT scan at Day 16 
(to address FDA comment from November 
2018 on SAP Version 1) 
27-SEP-2022 
3.0 
• GOSE/mRS: All GOSE/mRS analyses are now 
also adjusted for the partial neurological 
recovery variable (mGCS ≥ 14 and aNIHSS = 0, 
Yes/No). 
• Subgroup analyses for safety variables were 
added. 
• Minor updates/corrections/clarifications 
throughout the document. 
26-JAN-2023 
4.0 
• Name of the subgroup “partial neurological 
recovery” changed to “good neurological 
recovery subgroup”. 
• New table displaying main cause of death. 
• New table displaying SAS procedure outputs. 
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Version Date 
Version 
Implemented Change(s) 
• EQ-5D: Rule to reallocate visit was added. 
• Update definition of marked abnormalities for 
ALT and AST. 
• Minor updates/corrections/clarifications 
throughout the document. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; aNIHSS = abbreviated National Institutes of 
Health Stroke Scale; aSAH = aneurysmal subarachnoid hemorrhage; CT = computed tomography; 
EOS = End-of-Study; EQ-5D = Euro Quality of Life-5D; GOSE = Glasgow Outcome Scale – Extended; 
IDMC =Independent Data Monitoring Committee; mGCS = modified Glasgow Coma Scale; mRS = modified 
Rankin Scale; SAE = serious adverse event. 
 
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14.2 Schedule of events 
Visit and assessment schedule for subjects in the high-risk prevention group 
PERIOD 
 
Hospital 
admission 
SCREENING 
Period 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety FU  
Period 
Extended FU Period 
(From end of 24 h safety FU Period 
until EOS) 
TREATMENT Period 
(min. 10, max. 14 days of treatment)  
Timing / assessment 
within 96 hours post-aSAH 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS)19 
From ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start Daily in ICU8  
During observation 
period8 
Worsening of 
≥ 2 points on mGCS / 
aNIHSS8 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical history  
 
X 
X 
 
 
 
 
 
 
Incl./Excl. criteria 
 
X 
 
 
 
 
 
 
 
Height, weight 
 
X 
 
 
 
 
 
 
 
Vital signs (BP, HR, ICP1, 
CVP1) 
 
 
X  
(within 60 min) 
q6h 
(± 1 h) 
q6h (± 1 h)  
(every 12 h if not in 
ICU) 
 
 
 
 
Body temperature 
 
 
X  
(within 60 min) 
X  
(every 12 h ± 1 h)  
 
 
 
 
Fluid balance (24 h)16 
 
 
X 
X 
 
 
 
 
 
ECG parameters 
 
 
X 
(within 60 min) 
X9 
X (within 2 h 
post-SD stop) 
 
 
Laboratory tests  
(local [l]/ central [c]) 
 
X (l) 
X (c)  
(within 60 min) 
X10 (c) (EOD for 14 days)  
X (l) / SpO2 
X10 (c) (within 2 h 
post-SD stop)  
 
 
Biomarker  
 
 
X (c)  
(within 60 min) 
X (c) (EOD for 14 days) 
X (c) if CNS cause 
X (c) (within 2 h 
post-SD stop)  
 
 
Pregnancy test  
 
X (serum, (l)) 
 
 
 
 
 
X (urine) 
 
Concomitant 
medications18 
X  
 
X 
Non-drug treatments / 
interventions 
 
 
X 
X 
WFNS  
X2 
X, X3 
 
 
 
 
 
 
 
Total GCS 
X2 
X, X3 
 
 
 
 
 
 
 
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PERIOD 
 
Hospital 
admission 
SCREENING 
Period 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety FU  
Period 
Extended FU Period 
(From end of 24 h safety FU Period 
until EOS) 
TREATMENT Period 
(min. 10, max. 14 days of treatment)  
Timing / assessment 
within 96 hours post-aSAH 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS)19 
From ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start Daily in ICU8  
During observation 
period8 
Worsening of 
≥ 2 points on mGCS / 
aNIHSS8 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
mGCS/aNIHSS 
 
 
X  
(within 30 min) 
q6h11 
(± 1 h) 
X12 
(± 1 h) 
X  
(hourly ± 15 min for 
first 2 h) 
 
 
 
Angiogram  
(DSA or CTA) 
X4 
X  
(local standard-
of-care, not 
assessed 
centrally) 
 
 
 
X  
(if CNS cause) 
 
 
 
CT scan 
X4 
X5 
 
 
 
X  
(if CNS cause) 
X13 (16 days post-
SD start) 
 
 
Subject narrative 
 
 
 
 
 
X (14 days post-SD 
start) 
 
 
 
MoCA6 
 
X7 
 
X (14 ± 1 day post-SD 
start) 17 
 
 
X 
 
GOSE 
 
 
 
 
 
 
 
X 
 
SS-QoL, Ox-PAQ  
 
 
 
 
 
 
 
X 
 
EQ-5D 
 
 
 
 
 
 
 
 
X 
X 
Study drug administration 
 
 
 
X 
X 
 
 
 
 
 
Adverse events14 
 
X 
 
X 
Serious adverse events15 
 
X 
X 
Pharmaco-economic 
assessments 
 
 
X 
 
X 
 
Employment status 
 
 
 
 
 
X 
1. ICP/CVP will be measured and recorded for those subjects with ICP and/or CVP monitoring in place. 
2. If the subject was transferred from another hospital, the GCS score and WFNS grade will correspond to the assessments made at the referral hospital, unless these were not done or not reliable. 
3. Two assessments: post aneurysm-securing procedure and prior to randomization. 
4. If performed at a referral hospital, is of acceptable quality, and is available in digital format at the investigational site at the time of screening, does not need to be repeated. 
5. This CT scan is to be performed at least 8 hours after the aneurysm-securing procedure and within 24 hours prior to randomization. 
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6. Only performed if subject is GCS ≥ 13 and extubated (if applicable). 
7. As soon as possible after recovering from the aneurysm-securing procedure and prior to SD start.  
8. If there is a worsening of at least 2 points in the mGCS and/or the aNIHSS the assessments in the “worsening” column must be performed on top of the regularly scheduled assessments. The mGCS 
and the aNIHSS must be repeated hourly for at least the first 2 hours after a 2-point worsening. If the deterioration is believed to be of CNS origin, a cerebral angiogram and a cerebral CT scan must 
be performed within 6 hours of the start of the symptoms and submitted for central review and a blood sample for S100b protein must be drawn within 1 hour of the confirmation of the neurological 
deterioration episode or no later than 3 hours from the initial worsening. Local lab tests should be obtained as close as possible to the time of the clinical worsening (max. 1 hour after time of 
confirmed worsening) [See Section 7.2.2.2.1 for details]. 
9. QT, QRS, PR, RR intervals, and HR will be measured and recorded in the eCRF if subject experiences an AE related to cardiac rhythm abnormalities [see Section 7.2.3.7]. 
10. Any clinically significant laboratory values must be reported as an AE/SAE as appropriate and those still abnormal at the time of the EOS assessment will be followed up based on local routine 
standard-of-care. A local laboratory may be requested by the sponsor to document the event and its resolution, and the results recorded in the eCRF [see Section 7.2.4.1]. 
11. At least once per day for subjects that require uninterrupted continuous sedation. 
12. After the end of the study drug infusion, the mGCS and aNIHSS will continue to be assessed every 6 hours if the subject is still in the ICU (or equivalent ward), until 14 days after study drug 
initiation. They will be assessed at least once per day if the subject requires continuous uninterrupted sedation. If the subject is no longer in the ICU (i.e., has been sent to a regular/general ward), the 
mGCS and aNIHSS will be assessed at least once every 12 hours (± 1 h) until 14 days after study drug initiation. In the unavoidable situation where the subject is discharged from the study site before 
completing the observation period, their clinical status must be followed up to cover the period between discharge and Day 14 post-study drug start. The follow-up should be performed on Day 14 
post-study drug initiation or as soon as possible after. This follow-up is not required if the subject was discharged on Day 13 and there is at least one set of neurological assessment scales available on 
this day. 
13. If the CT scan cannot be performed on the 16th day post-SD start, then it is acceptable if the CT scan is performed up to 7 days after Day 16. The CT scan will be performed on the day of hospital 
discharge for those subjects who are discharged from the hospital prior to 16 days after study drug start. If no CT scan is available at hospital discharge, the last CT scan performed prior to discharge 
may be used for this assessment. For further details see Section 7.2.2.4.4. 
14. All AEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other AEs are to be reported from SD initiation until 24 hours 
post-permanent SD discontinuation. 
15. All SAEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other SAEs are to be reported from SD initiation until EOS. Waived 
SAEs do not require reporting to the sponsor’s Drug Safety department within 24 hours of the knowledge of its occurrence [see Section 9.1.3]. 
16. Applicable during study drug administration only. Balance is captured if a urine catheter is present. Otherwise, 24-hour fluid intake will be measured and recorded. 
17. This MoCA will be performed on the day of hospital discharge for those subjects who are discharged from the hospital prior to 14 days after study drug start. 
18. For details on the concomitant medication recording refer to Section 5.2.5. 
19. The EOS visit is conducted remotely as a telephone interview. 
AE = adverse event; aNIHSS = abbreviated National Institutes of Health Stroke Scale; aSAH = aneurysmal subarachnoid hemorrhage; BP = blood pressure; CNS = central nervous system; CT = computerized 
tomography; CTA = computerized tomography angiography; CVP = central venous pressure; DSA = digital subtraction angiography; ECG = electrocardiogram; eCRF = electronic case report form; EOD 
= every other day; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; GCS = Glasgow Coma Scale; GOSE = Glasgow Outcome Scale Extended; HR = heart rate; ICF = informed consent 
form; ICP = intracranial pressure; ICU = intensive care unit; mGCS = modified Glasgow Coma Scale; MoCA = Montreal Cognitive Assessment; Ox-PAQ = Oxford Participation and Activities 
Questionnaire; SAE = serious adverse event; SD = study drug; SpO2 = peripheral capillary oxygen saturation; SS-QoL = Stroke-Specific Quality of Life; WFNS = World Federation of Neurological 
Societies. 
 
 
 
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Visit and assessment schedule for subjects in the early treatment stratum (recruitment in this stratum was discontinued from protocol version 6, dated 
29 April 2021 onwards) 
PERIOD 
Hospital 
Admission  
SCREENING 
Period 
 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety 
FU Period  
Extended FU Period 
(From end of 24 h safety FU period 
until EOS) 
TREATMENT Period 
(min. 6, max. 14 days of treatment) 
Timing / assessment 
until max. Day 14 
post-aSAH 
within 24 h of pre-
randomization 
angiogram5 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS) 21 
from ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start 
Daily 
in ICU9  
During observation 
period9 
Worsening of  
≥ 2 points on 
mGCS / 
aNIHSS9 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical history  
 
X 
X 
 
 
 
 
 
 
Incl./Excl. criteria 
 
X 
 
 
 
 
 
 
 
Height, weight 
 
X 
 
 
 
 
 
 
 
Vital signs (BP, HR, ICP1, 
CVP1) 
 
 
X  
(within 60 min) 
q6h 
(± 1 h) 
q6h (± 1 h) 
(every 12 h if not in 
ICU) 
 
 
 
 
Body temperature 
 
 
X  
(within 60 min) 
X  
(every 12 h ± 1 h) 
 
 
 
 
Fluid balance (24 h)18 
 
 
X 
X 
 
 
 
 
 
ECG parameters 
 
 
X  
(within 60 min) 
X10 
X (within 2 h 
post-SD stop) 
 
 
Laboratory tests (local [l]/ 
central [c]) 
 
X (l) 
X (c)  
(within 60 min) 
X11 (c)  
(EOD for 14 days)  
X (l) /SpO2 
X11 (c) (within 2 h 
post-SD stop) 
 
 
Biomarker  
 
 
X (c) (within 60 
min) 
X (c) 
(EOD for 14 days)  
X (c) 
(if CNS cause) 
X (c) (within 2 h 
post-SD stop) 
 
 
Pregnancy test  
 
X (serum, (l)) 
 
 
 
 
 
X (urine) 
 
Concomitant medications20 
X  
X 
Non-drug treatments / 
interventions 
 
 
X 
X 
WFNS  
X2 
X, X3 
 
 
 
 
 
 
 
Total GCS 
X2 
X, X3 
 
 
 
 
 
 
 
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PERIOD 
Hospital 
Admission  
SCREENING 
Period 
 
 
OBSERVATION Period 
(for 14 days post-study drug initiation  
irrespective of treatment duration) 
24 h safety 
FU Period  
Extended FU Period 
(From end of 24 h safety FU period 
until EOS) 
TREATMENT Period 
(min. 6, max. 14 days of treatment) 
Timing / assessment 
until max. Day 14 
post-aSAH 
within 24 h of pre-
randomization 
angiogram5 
for 14 days  
post-SD start  
until 24 h post-SD 
stop  
WEEK 12 
VISIT 
END OF STUDY 
(EOS) 21 
from ICF to 
randomization 
Prior to study 
drug (SD) start 
SD 
start 
Daily 
in ICU9  
During observation 
period9 
Worsening of  
≥ 2 points on 
mGCS / 
aNIHSS9 
End-of-Treatment 
(EOT) 
84 days post-
aSAH ( 7 d) 
24 weeks (168 days 
± 14 days) 
post-aSAH 
mGCS/aNIHSS 
 
 
X  
(within 30 min) 
q6h12 
(± 1 h) 
X13 
(± 1 h) 
X  
(hourly ± 15 min 
for first 2 h) 
 
 
 
Angiogram  
(DSA or CTA) 
X4 
X17  
X5 
 
 
 
X 
(if CNS cause) 
 
 
 
CT scan 
X4 
X6 
 
 
 
X 
(if CNS cause) 
X14 (16 days 
post-SD start) 
 
 
Subject narrative 
 
 
 
 
 
X (14 days 
post-SD start) 
 
 
 
MoCA7 
 
X8 
 
X (14 ± 1 day 
post-SD start) 19 
 
 
X 
 
GOSE 
 
 
 
 
 
 
 
X 
 
SS-QoL, Ox-PAQ 
 
 
 
 
 
 
 
X 
 
EQ-5D 
 
 
 
 
 
 
 
 
X 
X 
Study drug administration 
 
 
 
X 
X 
 
 
 
 
 
Adverse events15 
 
X 
 
X 
Serious adverse events16 
 
X 
X 
Pharmaco-economic 
assessments 
 
 
X 
 
X 
 
Employment status 
 
 
 
 
 
X 
1. ICP/CVP will be measured and recorded for those subjects with ICP and/or CVP monitoring in place. 
2. If the subject was transferred from another hospital, the GCS score and WFNS grade will correspond to the assessments made at the referral hospital, unless these were not done or unreliable. 
3. Two assessments: post aneurysm-securing procedure and prior to randomization. 
4.  If performed at a referral hospital, is of acceptable quality, and is available in digital format at the investigational site at the time of screening, does not need to be repeated. 
5. The DSA or CTA which was performed according to local routine standard-of-care (preferably between Day 7 and 11 post-aSAH) and used to diagnose and document the vasospasm will be collected. 
6. This CT scan is to be performed at least 8 hours after the aneurysm-securing procedure and within 24 hours prior to randomization. 
7. Only performed if subject is GCS ≥ 13 and extubated (if applicable). 
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8. As soon as possible after recovering from the aneurysm-securing procedure and prior to SD start.  
9. If there is a worsening of at least 2 points in the mGCS and/or the aNIHSS the assessments in the “worsening” column must be performed on top of the regularly scheduled assessments. The mGCS 
and the aNIHSS must be repeated hourly for at least the first 2 hours after a 2-point worsening. If the deterioration is believed to be of CNS origin, a cerebral angiogram and a cerebral CT scan must 
be performed within 6 hours of the start of the symptoms and submitted for central review and a blood sample for S100b protein must be drawn within 1 hour of the confirmation of the neurological 
deterioration episode or no later than 3 hours from the initial worsening. Local lab tests should be obtained as close as possible to the time of the clinical worsening (max. 1 hour after time of 
confirmed worsening) [see Section 7.2.2.2.1 for details]. 
10. QT, QRS, PR, RR intervals, and HR will be measured and recorded in the eCRF if subject experiences an AE related to cardiac rhythm abnormalities [see Section 7.2.3.7]. 
11. Any clinically significant laboratory values must be reported as an AE/SAE as appropriate and those still abnormal at the time of the EOS assessment will be followed up based on local routine 
standard-of-care. A local laboratory may be requested by the sponsor to document the event and its resolution, and the results recorded in the eCRF [see Section 7.2.4.1]. 
12. At least once per day for subjects that require uninterrupted continuous sedation. 
13. After the end of the study drug infusion, the mGCS and aNIHSS will continue to be assessed every 6 hours if the subject is still in the ICU (or equivalent ward), until 14 days after study drug 
initiation. They will be assessed at least once per day if the subject requires continuous uninterrupted sedation. If the subject is no longer in the ICU (i.e., has been sent to a regular/general ward), the 
mGCS and aNIHSS will be assessed at least once every 12 hours (± 1 h) until 14 days after study drug initiation. In the unavoidable situation where the subject is discharged from the study site before 
completing the observation period, their clinical status must be followed up to cover the period between discharge and Day 14 post-study drug start. The follow-up should be performed on Day 14 
post-study drug initiation or as soon as possible after. This follow-up is not required if the subject was discharged on Day 13 and there is at least one set of neurological assessment scales available on 
this day.14. 
If the CT scan cannot be performed on the 16th day post-SD start, then it is acceptable if the CT scan is performed up to 7 days after Day 16. The CT scan will be performed on the day 
of hospital discharge for those subjects who are discharged from the hospital prior to 16 days after study drug start. If no CT scan is available at hospital discharge, the last CT scan performed prior to 
discharge may be used for this assessment. For further details see Section 7.2.2.4.4. 
15. All AEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other AEs are to be reported from SD initiation until 24 hours 
post-permanent SD discontinuation. 
16. All SAEs that occur after signing the ICF and up to the EOS visit must be recorded if related to a study-mandated procedure. All other SAEs are to be reported from SD initiation until EOS. Waived 
SAEs do not require reporting to the sponsor’s Drug Safety department within 24 hours of the knowledge of its occurrence [see Section 9.1.3]. 
17. Angiogram performed as per local standard-of-care to confirm successful aneurysm-securing procedure. Angiogram not assessed centrally. 
18. Applicable during study drug administration only. Balance is captured if a urine catheter is present. Otherwise, 24-hour fluid intake will be measured and recorded. 
19. This MoCA will be performed on the day of hospital discharge for those subjects who are discharged from the hospital prior to 14 days after study drug start. 
20. For details on the concomitant medication recording refer to Section 5.2.5. 
21. The EOS visit is conducted remotely as a telephone interview. 
AE= adverse event; aNIHSS = abbreviated National Institutes of Health Stroke Scale; aSAH = aneurysmal subarachnoid hemorrhage; BP = blood pressure; CNS = central nervous system; CT = 
computerized tomography; CTA = computerized tomography angiography; CVP = central venous pressure; DSA = digital subtraction angiography; ECG = electrocardiogram; eCRF = electronic case 
report form; EOD = every other day; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; GCS = Glasgow Coma Scale; GOSE = Glasgow Outcome Scale Extended; HR = heart rate; ICF 
= informed consent form; ICP = intracranial pressure; ICU = intensive care unit; mGCS = modified Glasgow Coma Scale; MoCA = Montreal Cognitive Assessment; Ox-PAQ = Oxford Participation 
and Activities Questionnaire; SAE = serious adverse event; SD = study drug; SpO2 = peripheral capillary oxygen saturation; SS-QoL = Stroke-Specific Quality of Life; WFNS = World Federation of 
Neurological Societies. 
 
 
 
 
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Clazosentan (ACT-108475) 
ID-054-304 (REACT) 
24 January 2023 
Confidential 
Statistical Analysis Plan for CSR 
Version 4 
Doc No D-23.039 
 
14.4 Adverse events of special interest 
This appendix contains the search criteria (provided as MedDRA PTs and PT codes) for 
the following AESIs: 
• Brain oedema 
• Cerebral hemorrhage 
• Anaemia 
• Lung complications 
• Hypotension 
• Oedema and fluid retention 
• Tachyarrhythmia 
• Hepatic disorders 
 
 
 
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Overview of search criteria for 
clazosentan AESI
MedDRA v25.0
Brain oedema
Cerebral hemorrhage
Anaemia
Lung complications
Hypotension
Oedema and fluid retention
Tachyarrhythmia
Hepatic disorders
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Intracranial haemorrhage neonatal
10086946
Intracranial tumour haemorrhage
10022775
Intraventricular haemorrhage
10022840
Intraventricular haemorrhage neonatal
10022841
Meningorrhagia
10052593
Perinatal stroke
10073945
Periventricular haemorrhage neonatal
10076706
Pituitary apoplexy
10056447
Pituitary haemorrhage
10049760
Putamen haemorrhage
10058940
Ruptured cerebral aneurysm
10039330
Spinal cord haematoma
10076051
Spinal cord haemorrhage
10048992
Spinal epidural haematoma
10050162
Spinal epidural haemorrhage
10049236
Spinal stroke
10082031
Spinal subarachnoid haemorrhage
10073564
Spinal subdural haematoma
10050164
Spinal subdural haemorrhage
10073563
Stroke in evolution
10059613
Subarachnoid haematoma
10076701
Subarachnoid haemorrhage
10042316
Subarachnoid haemorrhage neonatal
10042317
Subdural haematoma
10042361
Subdural haematoma evacuation
10042363
Subdural haemorrhage
10042364
Subdural haemorrhage neonatal
10042365
Thalamus haemorrhage
10058939
Vertebral artery perforation
10075735
Vertebrobasilar stroke
10082484
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Coombs negative haemolytic anaemia
10010940
Coombs positive haemolytic anaemia
10010941
Cytopenia
10066274
Deficiency anaemia
10061101
Erythroblast count abnormal
10058508
Erythroblast count decreased
10058505
Erythroid dysplasia
10086470
Erythroid maturation arrest
10015279
Erythropenia
10015287
Erythropoiesis abnormal
10049467
Erythropoietin deficiency anaemia
10083258
Febrile bone marrow aplasia
10053213
Foetal anaemia
10077577
Full blood count decreased
10017413
Gelatinous transformation of the bone marrow
10078097
Haematocrit abnormal
10049221
Haematocrit decreased
10018838
Haematotoxicity
10061188
Haemodilution
10059484
Haemoglobin abnormal
10018879
Haemoglobin decreased
10018884
Haemolytic anaemia
10018916
Haemolytic anaemia enzyme specific
10018919
Haemolytic icteroanaemia
10054920
Hand and foot syndrome secondary to sickle cell anaemia
10048775
Hereditary haemolytic anaemia
10060893
Hereditary microcytic anaemia
10085905
Hereditary sideroblastic anaemia
10019902
Hexokinase deficiency anaemia
10020022
Hyperchromic anaemia
10020605
Hypochromic anaemia
10020969
Hypoplastic anaemia
10021074
Immune-mediated cytopenia
10084828
Iron deficiency anaemia
10022972
Leukoerythroblastic anaemia
10053199
Microangiopathic haemolytic anaemia
10027527
Microcytic anaemia
10027538
Myelodysplastic syndrome
10028533
Myelodysplastic syndrome transformation
10067387
Myelofibrosis
10028537
Myeloid metaplasia
10028561
Myelosuppression
10028584
Nephrogenic anaemia
10058116
Normochromic anaemia
10029782
Normochromic normocytic anaemia
10029783
Normocytic anaemia
10029784
Pancytopenia
10033661
Panmyelopathy
10050026
Pernicious anaemia
10034695
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Plasmablast count decreased
10058774
Primary myelofibrosis
10077161
Proerythroblast count abnormal
10060227
Proerythroblast count decreased
10060229
Protein deficiency anaemia
10037006
Pyruvate kinase deficiency anaemia
10037682
Radiation anaemia
10085644
Red blood cell count abnormal
10038151
Red blood cell count decreased
10038153
Refractory anaemia with an excess of blasts
10038270
Refractory anaemia with ringed sideroblasts
10038272
Reticulocyte count abnormal
10038788
Reticulocyte count decreased
10038790
Reticulocyte percentage decreased
10059921
Reticulocytopenia
10038795
Scan bone marrow abnormal
10053504
Scorbutic anaemia
10086662
Sickle cell anaemia
10040641
Sickle cell anaemia with crisis
10040642
Sideroblastic anaemia
10040661
Spherocytic anaemia
10041509
Spur cell anaemia
10052483
Warm autoimmune haemolytic anaemia
10087091
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Cement embolism
10050484
Chronic respiratory failure
10009126
Chylothorax
10051228
Combined pulmonary fibrosis and emphysema
10076515
Complications of transplanted lung
10010187
Confirmed e-cigarette or vaping product use associated lung injury
10085189
Congenital chylothorax
10078770
Congenital emphysema
10010456
Congenital pneumonia
10010594
COPA syndrome
10083948
Coronavirus pneumonia
10084381
COVID-19 pneumonia
10084380
Cyanosis
10011703
Cyanosis central
10011704
Cystic lung disease
10078811
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
10082591
Embolic pneumonia
10065680
Emphysema
10014561
Engraftment syndrome
10050684
Enterobacter pneumonia
10054218
Eosinophilic pleural effusion
10080148
Eosinophilic pneumonia
10014962
Eosinophilic pneumonia acute
10052832
Eosinophilic pneumonia chronic
10052833
Haemorrhagic pneumonia
10077933
Haemothorax
10019027
Hepatic hydrothorax
10067365
Herpes simplex pneumonia
10065046
Hydrothorax
10048612
Hypercapnia
10020591
Hypercapnic coma
10072597
Hyperoxia
10058490
Hypobarism
10077606
Hypocapnia
10020952
Hypoxia
10021143
Hypoxia intolerance
10080129
Hypoxic ischaemic encephalopathy neonatal
10086943
Hypoxic-ischaemic encephalopathy
10070511
Idiopathic interstitial pneumonia
10078268
Idiopathic pneumonia syndrome
10063725
Idiopathic pulmonary fibrosis
10021240
Interstitial lung disease
10022611
Leukostasis syndrome
10074608
Low lung compliance
10086117
Lung consolidation
10025080
Lung cyst
10068749
Lung induration
10057261
Lung infiltration
10025102
Lung perforation
10076279
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Lymphangioleiomyomatosis
10049459
MacLeod's syndrome
10025375
Metapneumovirus pneumonia
10085550
Metastatic pulmonary embolism
10069909
Middle lobe syndrome
10056652
Miliary pneumonia
10055088
Multifocal micronodular pneumocyte hyperplasia
10057109
Negative pressure pulmonary oedema
10080589
Neonatal pneumonia
10053584
Neonatal pneumothorax
10082056
Neuroendocrine cell hyperplasia of infancy
10072968
Non-cardiogenic pulmonary oedema
10029538
Obstetrical pulmonary embolism
10029925
Oesophageal-pulmonary fistula
10083015
Organising pneumonia
10067472
Paracancerous pneumonia
10080986
Paraneoplastic pleural effusion
10075715
Parasitic pneumonia
10078883
Pleural effusion
10035598
Pleuroparenchymal fibroelastosis
10084305
Pleuroperitoneal communication
10068641
Pneumocystis jirovecii pneumonia
10073755
Pneumonia
10035664
Pneumonia acinetobacter
10079866
Pneumonia adenoviral
10035665
Pneumonia anthrax
10035667
Pneumonia aspiration
10035669
Pneumonia bacterial
10060946
Pneumonia bordetella
10035672
Pneumonia chlamydial
10035673
Pneumonia cryptococcal
10067565
Pneumonia cytomegaloviral
10035676
Pneumonia escherichia
10035699
Pneumonia fungal
10061354
Pneumonia haemophilus
10035702
Pneumonia herpes viral
10035703
Pneumonia influenzal
10035714
Pneumonia klebsiella
10035717
Pneumonia legionella
10035718
Pneumonia lipoid
10035720
Pneumonia measles
10035722
Pneumonia moraxella
10035723
Pneumonia mycoplasmal
10035724
Pneumonia necrotising
10055672
Pneumonia parainfluenzae viral
10035727
Pneumonia pneumococcal
10035728
Pneumonia proteus
10079867
Pneumonia pseudomonal
10035731
Pneumonia respiratory syncytial viral
10035732
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Pneumonia salmonella
10035733
Pneumonia serratia
10079868
Pneumonia staphylococcal
10035734
Pneumonia streptococcal
10035735
Pneumonia tularaemia
10035736
Pneumonia viral
10035737
Pneumothorax
10035759
Pneumothorax spontaneous
10035763
Pneumothorax traumatic
10035765
Polymer fume fever
10077266
Post procedural pneumonia
10066590
Post procedural pulmonary embolism
10063909
Postoperative respiratory distress
10054809
Postoperative respiratory failure
10072651
Probable e-cigarette or vaping product use associated lung injury
10085188
Procedural pneumothorax
10077574
Progressive massive fibrosis
10036805
Pulmonary air leakage
10067826
Pulmonary alveolar haemorrhage
10037313
Pulmonary alveolar microlithiasis
10037315
Pulmonary amyloidosis
10063945
Pulmonary artery thrombosis
10037340
Pulmonary atypical adenomatous hyperplasia
10084570
Pulmonary bullae rupture
10086936
Pulmonary calcification
10051200
Pulmonary cavitation
10051738
Pulmonary congestion
10037368
Pulmonary contusion
10037370
Pulmonary embolism
10037377
Pulmonary fibrosis
10037383
Pulmonary fistula
10065873
Pulmonary haemosiderosis
10037396
Pulmonary infarction
10037410
Pulmonary interstitial emphysema syndrome
10037415
Pulmonary microemboli
10037421
Pulmonary necrosis
10058824
Pulmonary nodular lymphoid hyperplasia
10077412
Pulmonary oedema
10037423
Pulmonary oedema neonatal
10050459
Pulmonary oedema post fume inhalation
10037427
Pulmonary oil microembolism
10069388
Pulmonary ossification
10070310
Pulmonary pneumatocele
10063749
Pulmonary thrombosis
10037437
Pulmonary toxicity
10061924
Pulmonary tumour thrombotic microangiopathy
10079988
Pulmonary venous thrombosis
10037459
Reexpansion pulmonary oedema
10064715
Respiratory acidosis
10038661
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Respiratory alkalosis
10038664
Respiratory failure
10038695
Respiratory gas exchange disorder
10062105
Respiratory paralysis
10038708
Restrictive allograft syndrome
10077506
Restrictive pulmonary disease
10048667
Rheumatoid arthritis-associated interstitial lung disease
10085517
Septic pulmonary embolism
10083093
Transfusion-related acute lung injury
10052235
Traumatic haemothorax
10074487
Traumatic lung injury
10069363
Unilateral bronchospasm
10072338
Varicella zoster pneumonia
10074254
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Heat oedema
10019340
Hydraemia
10060374
Hydrothorax
10048612
Hydrovarium
10081546
Hypervolaemia
10020919
Hypoosmolar state
10074867
Implant site oedema
10063776
Implant site swelling
10063867
Inadequate peritoneal dialysis
10085005
Incision site oedema
10065614
Incision site swelling
10074758
Infusion site joint effusion
10076072
Infusion site joint swelling
10076078
Infusion site oedema
10053998
Infusion site swelling
10053505
Injection site joint swelling
10049260
Injection site oedema
10022085
Injection site swelling
10053425
Instillation site oedema
10073619
Joint effusion
10023215
Joint swelling
10023232
Lipoedema
10063955
Localised oedema
10048961
Lumbar subcutaneous oedema
10086593
Lymphoedema
10025282
Lymphovenous bypass
10084980
Medical device site joint effusion
10076117
Medical device site joint swelling
10076123
Modified Rodnan skin score abnormal
10081776
Mouth swelling
10075203
Muscle oedema
10071759
Muscle swelling
10064470
Myocardial oedema
10064966
Negative pressure pulmonary oedema
10080589
Non-cardiogenic pulmonary oedema
10029538
Non-pitting oedema
10083903
Oedema
10030095
Oedema blister
10080039
Oedema due to cardiac disease
10049632
Oedema due to hepatic disease
10049631
Oedema due to renal disease
10049630
Oedema mucosal
10030111
Oedema neonatal
10061317
Oedema peripheral
10030124
Oedematous kidney
10073381
Oesophageal oedema
10064342
Omental oedema
10087030
Oropharyngeal oedema
10078783
Pelvic fluid collection
10065388
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Pericardial effusion
10034474
Perinephric collection
10059209
Perinephric oedema
10078818
Peripheral oedema neonatal
10049779
Peripheral swelling
10048959
Pleural effusion
10035598
Prevertebral soft tissue swelling of cervical space
10074880
Pulmonary oedema
10037423
Pulmonary oedema neonatal
10050459
Puncture site oedema
10074069
Reexpansion pulmonary oedema
10064715
Retroperitoneal effusion
10063637
Retroperitoneal oedema
10038983
Scleroedema
10055953
Second impact syndrome
10084563
Skin oedema
10058679
Skin swelling
10053262
Spinal cord oedema
10063036
Subdural effusion
10054797
Swelling
10042674
Swelling face
10042682
Swelling of eyelid
10042690
Tendon sheath effusion
10086724
Testicular swelling
10043354
Vaccination site joint effusion
10076172
Vaccination site joint swelling
10076178
Vasogenic cerebral oedema
10067275
Visceral oedema
10065768
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Junctional ectopic tachycardia
10074640
Parasystole
10033929
Retrograde p-waves
10071187
Rhythm idioventricular
10039111
Sinus tachycardia
10040752
Supraventricular extrasystoles
10042602
Supraventricular tachyarrhythmia
10065342
Supraventricular tachycardia
10042604
Tachyarrhythmia
10049447
Torsade de pointes
10044066
Ventricular arrhythmia
10047281
Ventricular extrasystoles
10047289
Ventricular fibrillation
10047290
Ventricular flutter
10047294
Ventricular parasystole
10058184
Ventricular pre-excitation
10049761
Ventricular tachyarrhythmia
10065341
Ventricular tachycardia
10047302
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Benign hepatobiliary neoplasm
10077922
Benign recurrent intrahepatic cholestasis
10087038
Bile output abnormal
10051344
Bile output decreased
10051343
Biliary ascites
10074150
Biliary cirrhosis
10004659
Biliary fibrosis
10004664
Bilirubin conjugated abnormal
10067718
Bilirubin conjugated increased
10004685
Bilirubin excretion disorder
10061009
Bilirubin urine present
10077356
Biopsy liver abnormal
10004792
Blood alkaline phosphatase abnormal
10059571
Blood alkaline phosphatase increased
10059570
Blood bilirubin abnormal
10058477
Blood bilirubin increased
10005364
Blood bilirubin unconjugated increased
10005370
Blood cholinesterase abnormal
10005429
Blood cholinesterase decreased
10005430
Blood fibrinogen abnormal
10005518
Blood fibrinogen decreased
10005520
Blood thrombin abnormal
10005818
Blood thrombin decreased
10005820
Blood thromboplastin abnormal
10005824
Blood thromboplastin decreased
10005826
Bromosulphthalein test abnormal
10006408
Cardiohepatic syndrome
10082480
Cerebrohepatorenal syndrome
10053684
Child-Pugh-Turcotte score abnormal
10077020
Child-Pugh-Turcotte score increased
10068287
Cholaemia
10048611
Cholangiosarcoma
10077861
Cholestasis
10008635
Cholestasis of pregnancy
10049055
Cholestatic liver injury
10067969
Cholestatic pruritus
10064190
Chronic graft versus host disease in liver
10072160
Chronic hepatic failure
10057573
Chronic hepatitis
10008909
Chronic hepatitis B
10008910
Chronic hepatitis C
10008912
Cirrhosis alcoholic
10009208
Coagulation factor decreased
10009736
Coagulation factor IX level abnormal
10061770
Coagulation factor IX level decreased
10009746
Coagulation factor V level abnormal
10061771
Coagulation factor V level decreased
10009754
Coagulation factor VII level abnormal
10061772
Coagulation factor VII level decreased
10009761
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Coagulation factor X level abnormal
10061774
Coagulation factor X level decreased
10009775
Coma hepatic
10010075
Complications of transplanted liver
10010186
Computerised tomogram liver abnormal
10078360
Congenital absence of bile ducts
10010317
Congenital hepatic fibrosis
10056533
Congenital hepatitis B infection
10010496
Congenital hepatitis C infection
10084252
Congenital hepatobiliary anomaly
10061065
Congenital hepatomegaly
10051130
Congenital viral hepatitis
10084251
Congestive hepatopathy
10084058
Cryptogenic cirrhosis
10063075
Cystic fibrosis hepatic disease
10068289
Cytokeratin 18 increased
10068471
Cytomegalovirus hepatitis
10011830
Deficiency of bile secretion
10071634
Diabetic hepatopathy
10071265
Dilatation intrahepatic duct congenital
10013003
Drug-induced liver injury
10072268
Duodenal varices
10051010
Fatty liver alcoholic
10016262
Flood syndrome
10084797
Focal nodular hyperplasia
10052285
Foetor hepaticus
10052554
Galactose elimination capacity test abnormal
10059710
Galactose elimination capacity test decreased
10059712
Gallbladder varices
10072319
Gamma-glutamyltransferase abnormal
10017688
Gamma-glutamyltransferase increased
10017693
Gastric variceal injection
10076237
Gastric variceal ligation
10076238
Gastric varices
10051012
Gastric varices haemorrhage
10057572
Gastrooesophageal variceal haemorrhage prophylaxis
10066597
Gianotti-Crosti syndrome
10053842
Glutamate dehydrogenase increased
10049483
Glycocholic acid increased
10080824
Glycogen storage disease type I
10018464
Glycogen storage disease type III
10053250
Glycogen storage disease type IV
10053249
Glycogen storage disease type VI
10053240
Graft versus host disease in liver
10064676
Granulomatous liver disease
10018704
Guanase increased
10051333
Haemangioma of liver
10018821
Haemorrhagic ascites
10059766
Haemorrhagic hepatic cyst
10067796
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HBV-DNA polymerase increased
10058937
Hepaplastin abnormal
10019621
Hepaplastin decreased
10019622
Hepatectomy
10061997
Hepatic adenoma
10019629
Hepatic amoebiasis
10063741
Hepatic angiosarcoma
10067388
Hepatic artery flow decreased
10068997
Hepatic atrophy
10019637
Hepatic calcification
10065274
Hepatic cancer
10073069
Hepatic cancer metastatic
10055110
Hepatic cancer recurrent
10073070
Hepatic cancer stage I
10059318
Hepatic cancer stage II
10059319
Hepatic cancer stage III
10059324
Hepatic cancer stage IV
10059325
Hepatic candidiasis
10049653
Hepatic cirrhosis
10019641
Hepatic cyst
10019646
Hepatic cyst infection
10051705
Hepatic cyst ruptured
10053973
Hepatic cytolysis
10049199
Hepatic echinococciasis
10019659
Hepatic encephalopathy
10019660
Hepatic encephalopathy prophylaxis
10066599
Hepatic enzyme abnormal
10062685
Hepatic enzyme decreased
10060794
Hepatic enzyme increased
10060795
Hepatic failure
10019663
Hepatic fibrosis
10019668
Hepatic fibrosis marker abnormal
10074084
Hepatic fibrosis marker increased
10074413
Hepatic function abnormal
10019670
Hepatic gas gangrene
10077055
Hepatic haemangioma rupture
10054885
Hepatic hamartoma
10079685
Hepatic hydrothorax
10067365
Hepatic hypertrophy
10076254
Hepatic hypoperfusion
10084751
Hepatic infection
10056522
Hepatic infection bacterial
10065215
Hepatic infection fungal
10065217
Hepatic infection helminthic
10065216
Hepatic infiltration eosinophilic
10064668
Hepatic lesion
10061998
Hepatic lipoma
10086088
Hepatic lymphocytic infiltration
10079686
Hepatic mass
10057110
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Hepatic necrosis
10019692
Hepatic neoplasm
10019695
Hepatic neuroendocrine tumour
10085864
Hepatic pain
10019705
Hepatic perfusion disorder
10083840
Hepatic sarcoma
10086958
Hepatic sequestration
10066244
Hepatic steato-fibrosis
10077215
Hepatic steatosis
10019708
Hepatic vascular resistance increased
10068358
Hepatic venous pressure gradient abnormal
10083172
Hepatic venous pressure gradient increased
10083171
Hepatitis
10019717
Hepatitis A
10019719
Hepatitis A antibody abnormal
10019722
Hepatitis A antibody positive
10019725
Hepatitis A antigen positive
10058751
Hepatitis A immunity confirmed
10086044
Hepatitis A virus test positive
10070216
Hepatitis acute
10019727
Hepatitis alcoholic
10019728
Hepatitis B
10019731
Hepatitis B antibody abnormal
10019733
Hepatitis B antibody positive
10019736
Hepatitis B antigen positive
10063411
Hepatitis B core antibody positive
10071344
Hepatitis B core antigen positive
10052328
Hepatitis B DNA assay positive
10060047
Hepatitis B DNA increased
10068379
Hepatitis B e antibody positive
10071348
Hepatitis B e antigen positive
10052329
Hepatitis B immunity confirmed
10086043
Hepatitis B reactivation
10058827
Hepatitis B surface antibody positive
10071346
Hepatitis B surface antigen positive
10019742
Hepatitis B virus test positive
10070217
Hepatitis C
10019744
Hepatitis C antibody positive
10019747
Hepatitis C core antibody positive
10077052
Hepatitis C RNA increased
10068377
Hepatitis C RNA positive
10019750
Hepatitis C virus test positive
10070218
Hepatitis cholestatic
10019754
Hepatitis chronic active
10019755
Hepatitis chronic persistent
10019759
Hepatitis D
10019762
Hepatitis D antibody positive
10059528
Hepatitis D antigen positive
10058436
Hepatitis D RNA positive
10059540
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Hepatitis D virus test positive
10070626
Hepatitis E
10019768
Hepatitis E antibody abnormal
10057994
Hepatitis E antibody positive
10057985
Hepatitis E antigen positive
10060049
Hepatitis E immunity confirmed
10086045
Hepatitis E RNA positive
10086906
Hepatitis E virus test positive
10070220
Hepatitis F
10019771
Hepatitis fulminant
10019772
Hepatitis G
10019773
Hepatitis H
10019776
Hepatitis infectious mononucleosis
10019781
Hepatitis mumps
10019783
Hepatitis neonatal
10019785
Hepatitis non-A non-B
10019786
Hepatitis non-A non-B non-C
10019787
Hepatitis post transfusion
10019791
Hepatitis syphilitic
10019794
Hepatitis toxic
10019795
Hepatitis toxoplasmal
10019798
Hepatitis viral
10019799
Hepatitis viral test positive
10072748
Hepatobiliary cancer
10073073
Hepatobiliary cancer in situ
10073074
Hepatobiliary cyst
10079889
Hepatobiliary disease
10062000
Hepatobiliary infection
10056523
Hepatobiliary neoplasm
10061203
Hepatobiliary scan abnormal
10066195
Hepatoblastoma
10062001
Hepatoblastoma recurrent
10019823
Hepatocellular carcinoma
10073071
Hepatocellular damage neonatal
10019834
Hepatocellular foamy cell syndrome
10053244
Hepatocellular injury
10019837
Hepato-lenticular degeneration
10019819
Hepatomegaly
10019842
Hepatopulmonary syndrome
10052274
Hepatorenal failure
10019845
Hepatorenal syndrome
10019846
Hepatosplenic abscess
10077631
Hepatosplenic candidiasis
10051590
Hepatosplenomegaly
10019847
Hepatosplenomegaly neonatal
10019848
Hepatotoxicity
10019851
Hereditary haemochromatosis
10057873
Herpes simplex hepatitis
10067389
Hyperammonaemia
10020575
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Hyperbilirubinaemia
10020578
Hyperbilirubinaemia neonatal
10020580
Hypercholia
10051924
Hyperfibrinolysis
10074737
Hypertransaminasaemia
10068237
Hypoalbuminaemia
10020942
Hypocoagulable state
10020973
Hypofibrinogenaemia
10051125
Hypoprothrombinaemia
10021085
Hypothrombinaemia
10058517
Hypothromboplastinaemia
10058518
Icterus index increased
10021209
Immune-mediated cholangitis
10083406
Immune-mediated hepatic disorder
10083521
Immune-mediated hepatitis
10078962
Increased liver stiffness
10082444
International normalised ratio abnormal
10022592
International normalised ratio increased
10022595
Intestinal varices
10071502
Intestinal varices haemorrhage
10078058
Intrahepatic portal hepatic venous fistula
10072629
Ischaemic hepatitis
10023025
Jaundice
10023126
Jaundice cholestatic
10023129
Jaundice hepatocellular
10023136
Jaundice neonatal
10023138
Kayser-Fleischer ring
10023321
Kernicterus
10023376
Leucine aminopeptidase increased
10024275
Liver abscess
10024652
Liver and pancreas transplant rejection
10051603
Liver carcinoma ruptured
10050842
Liver dialysis
10076640
Liver disorder
10024670
Liver function test abnormal
10024690
Liver function test decreased
10077677
Liver function test increased
10077692
Liver induration
10052550
Liver injury
10067125
Liver iron concentration abnormal
10074352
Liver iron concentration increased
10074354
Liver opacity
10084071
Liver operation
10062040
Liver palpable
10075895
Liver sarcoidosis
10068664
Liver scan abnormal
10061947
Liver tenderness
10024712
Liver transplant
10024714
Liver transplant failure
10083175
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Liver transplant rejection
10024715
Liver-kidney microsomal antibody positive
10060107
Lupoid hepatic cirrhosis
10025129
Lupus hepatitis
10067737
Magnetic resonance imaging hepatobiliary abnormal
10085121
Magnetic resonance proton density fat fraction measuremen
10082443
Mitochondrial aspartate aminotransferase increased
10064712
Mixed hepatocellular cholangiocarcinoma
10027761
Mixed liver injury
10066758
Model for end stage liver disease score abnormal
10077291
Model for end stage liver disease score increased
10077292
Molar ratio of total branched-chain amino acid to tyrosine
10066869
Multivisceral transplantation
10082450
Necrolytic acral erythema
10084061
Neonatal cholestasis
10056528
Neonatal hepatomegaly
10049995
Nodular regenerative hyperplasia
10051081
Non-alcoholic fatty liver
10029530
Non-alcoholic steatohepatitis
10053219
Non-cirrhotic portal hypertension
10077259
Ocular icterus
10058117
Oedema due to hepatic disease
10049631
Oesophageal varices haemorrhage
10030210
Omental oedema
10087030
Osteopontin increased
10082708
Parenteral nutrition associated liver disease
10074151
Perihepatic discomfort
10054125
Perinatal HBV infection
10075233
Peripancreatic varices
10073215
Periportal oedema
10068821
Peritoneal fluid protein abnormal
10069000
Peritoneal fluid protein decreased
10068999
Peritoneal fluid protein increased
10068998
Peritoneovenous shunt
10052716
Pneumobilia
10066004
Polycystic liver disease
10048834
Porphyria acute
10036182
Porphyria non-acute
10036186
Portal fibrosis
10074726
Portal hypertension
10036200
Portal hypertensive colopathy
10079446
Portal hypertensive enteropathy
10068923
Portal hypertensive gastropathy
10050897
Portal pyaemia
10036202
Portal shunt
10036204
Portal shunt procedure
10077479
Portal tract inflammation
10075331
Portal vein cavernous transformation
10073979
Portal vein dilatation
10073209
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Portal vein flow decreased
10067337
Portal vein pressure increased
10064936
Portal venous system anomaly
10076609
Portopulmonary hypertension
10067281
Primary biliary cholangitis
10080429
Progressive familial intrahepatic cholestasis
10076033
Protein C decreased
10037005
Protein S abnormal
10051736
Protein S decreased
10051120
Prothrombin level abnormal
10037048
Prothrombin level decreased
10037050
Prothrombin time abnormal
10037057
Prothrombin time prolonged
10037063
Prothrombin time ratio abnormal
10061918
Prothrombin time ratio increased
10037068
Radiation hepatitis
10051015
Regenerative siderotic hepatic nodule
10080679
Renal and liver transplant
10052279
Retinol binding protein decreased
10048473
Retrograde portal vein flow
10067338
Reye's syndrome
10039012
Reynold's syndrome
10070953
Schistosomiasis liver
10039610
Small-for-size liver syndrome
10069380
Spider naevus
10041519
Splenic artery embolisation
10083795
Splenic varices
10067823
Splenic varices haemorrhage
10068662
Splenorenal shunt
10041661
Splenorenal shunt procedure
10077281
Spontaneous bacterial peritonitis
10061135
Spontaneous intrahepatic portosystemic venous shunt
10076239
Steatohepatitis
10076331
Stomal varices
10075186
Subacute hepatic failure
10056956
Sugiura procedure
10083010
Sustained viral response
10076041
Thrombin time abnormal
10051319
Thrombin time prolonged
10051390
Total bile acids increased
10064558
Transaminases abnormal
10062688
Transaminases increased
10054889
Ultrasound liver abnormal
10045428
Urine bilirubin increased
10050792
Urobilinogen urine decreased
10070480
Urobilinogen urine increased
10070479
Varices oesophageal
10056091
Varicose veins of abdominal wall
10072284
Viral hepatitis carrier
10047458
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Weil's disease
10047903
White nipple sign
10078438
Withdrawal hepatitis
10071220
X-ray hepatobiliary abnormal
10056536
Yellow skin
10048245
Zieve syndrome
10048255
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Clazosentan (ACT-108475) 
ID-054-304 (REACT) 
24 January 2023 
Confidential 
Statistical Analysis Plan for CSR 
Version 4 
Doc No D-23.039 
 
14.5 Definitions of marked abnormalities  
Where more than one assessment falls on the same day, the scheduled assessment is used 
above any non-scheduled (repeat or re-test or local) assessment for that parameter. 
Laboratory analyses are based central laboratory data.  
Marked laboratory abnormalities are displayed in Table 9, as described in the company 
standards  
Table 9 
Marked abnormalities in laboratory parameters for reporting  
Laboratory parameter 
Criteria for marked laboratory abnormalities 
Hematology (SI unit) 
Hemoglobin (g/L) 
< 80 
< 100 
> 20 above ULN or > 20 above baseline if baseline > ULN  
> 40 above ULN or > 40 above baseline if baseline > ULN  
Hematocrit (L/L) 
< 0.20 
< 0.32 (Male) or < 0.28 (Female)  
> 0.60 (Male) or > 0.55 (Female)  
> 0.65 
Platelets (109/L) 
< 50  
< 75  
> 600  
> 999  
Leukocytes (109/L) 
< 2.0  
< 3.0  
> 20.0  
> 100.0  
Lymphocytes (109/L) 
< 0.5 
< 0.8 
> 4.0 
> 20.0 
Blood chemistry (SI unit) 
Alkaline phosphatase (U/L) 
> 2.5 × ULN 
> 5 × ULN 
Alanine aminotransferase 
(U/L) 
> 3 × ULN 
> 5 × ULN 
> 8 × ULN 
> 10 × ULN 
Aspartate aminotransferase 
(U/L) 
> 3 × ULN 
> 5 × ULN 
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Clazosentan (ACT-108475) 
ID-054-304 (REACT) 
24 January 2023 
Confidential 
Statistical Analysis Plan for CSR 
Version 4 
Doc No D-23.039 
 
Laboratory parameter 
Criteria for marked laboratory abnormalities 
> 8 × ULN 
> 10 × ULN 
Total bilirubin (mol/L) 
> 2 × ULN 
> 5 × ULN 
Creatinine (mol/L) 
> 1.5 × ULN or > 1.5 × baseline if baseline < ULN 
> 3 × ULN or > 3 × baseline if baseline < ULN 
Potassium (mmol/L) 
< 3.0 
< 3.2 
> 5.5 
> 6.0 
Sodium (mmol/L) 
< 130 
> 150 
> 155 
Gamma-glutamyl 
transferase (U/L) 
> 2.5 × ULN 
> 5 × ULN 
Urea nitrogen (mmol/L) 
> 2.5 × ULN 
> 5 × ULN 
SI = standard international; ULN = upper limit of normal.  
 
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