Is Adding Cilostazol to Nimodipine Improving Neurological Outcome of Patients With Aneurysmal Subarachnoid Hemorrhage? A Randomized, Double Blind, Placebo-controlled Trial
Phase: PHASE3
Conditions: Aneurysmal Subarachnoid Hemorrhage
Sponsor: Centre Hospitalier St Anne

 
 
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Is adding Cilostazol to nimodipine improving 
neurological outcome of patients with Aneurysmal 
Subarachnoid Hemorrhage? A randomized, double 
blind, placebo-controlled trial 
CASH 
 
BIOMEDICAL RESEARCH PROTOCOL RELATING TO 
A MEDICINAL PRODUCT FOR HUMAN USE 
 
Version N°2.1 of 04/04/2025 
Project Code : D24-P009/EU Clinical Trials number : 2024-516468-27-00 
 
 
 
Coordinating Investigator :    Dr Caroline SCHIMPF 
 
 
 
 
Service d’Anesthésie Réanimation 
 
 
 
 
GHU Paris Psychiatrie et Neurosciences 
Tel.01 45 65 74 13 
Email c.schimpf@ghu-paris.fr 
 
Scientific Director :                Dr Aurélien MAZERAUD 
Service d’Anesthésie Réanimation 
GHU Paris Psychiatrie et Neurosciences 
Tel.01 45 65 74 13 
Email a.mazeraud@ghu-paris.fr 
 
Biostatistician :                      Isabelle DUFAURE-GARE 
Clinical Research and Innovation Office (DRCI) 
 
 
 
 
1 rue Cabanis 75674 PARIS Cedex 14 
Tel.01 45 65 62 66 
Email isabelle.dufaure-gare@ghu-paris.fr 
 
 
 
 
Sponsor : 
 
 
Le GHU Paris Psychiatrie et Neurosciences 
Dr. Khaoussou SYLLA 
Clinical Research and Innovation Office (DRCI) 
 
 
 
 
1 rue Cabanis 75674 PARIS Cedex 14 
 
 
 
 
 
 
Entity responsible  
for monitoring research : 
Le GHU Paris Psychiatrie et Neurosciences 
Dr. Khaoussou SYLLA 
Clinical Research and Innovation Office (DRCI) 
 
 
 
 
1 rue Cabanis 75674 PARIS Cedex 14 
 
 

 
 
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SIGNATURE page for a biomedical research PROTOCOL 
 
 
Research Research Code: D24-P009 
EU Clinical Trials number: 2024-516468-27-00 
Title: Is adding Cilostazol to nimodipine improving neurological outcome of patients with 
Aneurysmal Subarachnoid Hemorrhage? A randomized, double blind, placebo-controlled trial 
 
Version N° 2.1 of 04/04/2025                 
 
The clinical trial will be conducted in compliance with the protocol, with the EU Clinical 
Trials Regulation No. 536/2014 and with the principles of good clinical practice. 
 
 
Coordinating Investigator:  
 
Dr Caroline SCHIMPF  
Service d’Anesthésie Réanimation 
GHU Paris Psychietrie et Neurosciences 
Paris 
 
Date: ……………/………/……….. 
Signature: 
 
 
Scientific Director: 
 
Dr Aurélien MAZERAUD 
Service d’Anesthésie Réanimation 
GHU Paris Psychietrie et Neurosciences 
Paris 
 
Biostatistician 
 
Mme Isabelle DUFAURE-GARE 
Clinical Research and Innovation Office (DRCI) 
Le GHU Paris Psychiatrie et Neurosciences 
1 rue Cabanis 75674 PARIS Cedex 14 
 
 
Sponsor 
Date: ……………/………/……….. 
Signature: 
 
Docteur Khaoussou SYLLA 
Clinical Research and Innovation Office (DRCI) 
Le GHU Paris Psychiatrie et Neurosciences 
1 rue Cabanis 75674 PARIS Cedex 14 
 
Date: ……………/………/……….. 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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CONTENTS 
1 
SUMMARY ............................................................................................................................ 6 
2 
SCIENTIFIC JUSTIFICATION FOR THE RESEARCH ........................................................ 8 
2.1 
HYPOTHESIS FOR THE RESEARCH .............................................................................................. 9 
2.2 
DESCRIPTION OF KNOWLEDGE RELATING TO THE PATHOLOGY IN QUESTION ................................. 9 
2.3 
SUMMARY OF RELEVANT PRE-CLINICAL EXPERIMENTS AND CLINICAL TRIALS ................................. 9 
2.4 
DESCRIPTION OF THE POPULATION TO BE STUDIED AND JUSTIFICATION FOR THE CHOICE OF 
PARTICIPANTS ........................................................................................................................ 16 
2.5 
IDENTIFICATION AND DESCRIPTION OF THE EXPERIMENTAL MEDICATION OR MEDICATIONS ........... 16 
2.6 
DESCRIPTION AND JUSTIFICATION OF THE DOSAGE, ADMINISTRATION METHOD, ADMINISTRATION 
DESIGN AND TREATMENT PERIOD. ........................................................................................... 16 
2.7 
SUMMARY OF THE KNOWN AND FORESEEABLE BENEFITS AND RISKS FOR THE RESEARCH 
PARTICIPANTS ........................................................................................................................ 16 
3 
OBJECTIVES ...................................................................................................................... 11 
3.1 
PRIMARY OBJECTIVE ............................................................................................................... 11 
3.2 
SECONDARY OBJECTIVES ........................................................................................................ 11 
4 
PLAN FOR THE RESEARCH ............................................................................................. 19 
4.1 
CONCISE DESCRIPTION OF THE PRIMARY AND SECONDARY ASSESSMENT CRITERIA ..................... 19 
4.2 
DESCRIPTION OF RESEARCH METHODOLOGY ............................................................................ 20 
5 
PROCEDURE FOR THE RESEARCH ............................................................................... 20 
5.1 
INCLUSION VISIT ..................................................................................................................... 17 
5.2 
FOLLOW-UP VISITS ................................................................................................................. 19 
5.3 
END OF RESEARCH VISIT ......................................................................................................... 20 
5.4 
EXPECTED LENGTH OF PARTICIPATION AND DESCRIPTION OF THE CHRONOLOGY AND DURATION OF 
THE RESEARCH. ..................................................................................................................... 20 
5.5 
TABLE OR DIAGRAM SUMMARISING THE CHRONOLOGY OF THE RESEARCH .................................. 20 
     5.6       DEFINITION OF THE END OF THE TRIAL……………………………………………………. 20  
5.7 
DISTINCTION BETWEEN CARE AND RESEARCH ........................................................................... 20 
5.8 
TERMINATION RULES ............................................................................................................... 20 
6 
ELIGIBILITY CRITERIA ...................................................................................................... 22 
6.1 
INCLUSION CRITERIA ............................................................................................................... 22 
6.2 
NON-INCLUSION CRITERIA ....................................................................................................... 22 
6.3 
RECRUITMENT METHODS ......................................................................................................... 22 
7 
TREATMENT ADMINISTERED TO RESEARCH PARTICIPANTS ................................... 23 
7.1 
DESCRIPTION OF THE EXPERIMENTAL MEDICATION OR MEDICATIONS ......................................... 23 
7.2 
DESCRIPTION OF THE NON-EXPERIMENTAL TREATMENT OR TREATMENTS (MEDICATIONS REQUIRED 
FOR CARRYING OUT THE RESEARCH) ....................................................................................... 23 
7.3 
DESCRIPTION OF THE TRACEABILITY ELEMENTS THAT ACCOMPANY THE EXPERIMENTAL MEDICATION 
OR MEDICATIONS .................................................................................................................... 23 
7.4 
AUTHORISED AND PROHIBITED TREATMENTS (MEDICINAL, NON MEDICINAL, SURGICAL), INCLUDING 
RESCUE MEDICATIONS ............................................................................................................ 24 
7.5 
METHODS FOR MONITORING COMPLIANCE WITH THE TREATMENT .............................................. 24 
8 
ASSESSMENT OF EFFICACY ........................................................................................... 24 
8.1 
DESCRIPTION OF PARAMETERS FOR ASSESSING EFFICACY ........................................................ 24 
8.2 
ANTICIPATED METHODS AND TIMETABLE FOR MEASURING, COLLECTING AND ANALYSING THE 
PARAMETERS FOR ASSESSING EFFICACY ................................................................................. 25 
9 
SPECIFIC RESEARCH COMMITTEES .............................................................................. 25 
9.1 
SCIENTIFIC COMMITTEE ........................................................................................................... 25 
9.2 
STEERING COMMITTEE ............................................................................................................ 26 

 
 
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9.3 
ENDPOINT ADJUDICATION COMMITTEE ..................................................................................... 26 
10 
SAFETY ASSESSMENT - RISKS AND RESTRICTIONS ADDED BY THE RESEARCH 26 
10.1 
DESCRIPTION OF PARAMETERS FOR ASSESSING SAFETY ........................................................... 28 
10.2 
ANTICIPATED METHODS AND TIMETABLE FOR MEASURING, COLLECTING AND ANALYSING THE 
PARAMETERS FOR ASSESSING SAFETY .................................................................................... 28 
10.3 
PROCEDURES IN PLACE FOR RECORDING AND REPORTING ADVERSE EVENTS ............................. 29 
11 
DATA MANAGEMENT ....................................................................................................... 34 
11.1 
DATA COLLECTION METHODS ................................................................................................... 34 
11.2 
IDENTIFICATION OF DATA COLLECTED DIRECTLY IN THE CRFS AND THAT WILL BE CONSIDERED AS 
SOURCE DATA ........................................................................................................................ 34 
11.3 
RIGHT TO ACCESS SOURCE DATA AND DOCUMENTS .................................................................. 34 
11.4 
DATA PROCESSING AND STORAGE OF DOCUMENTS AND DATA ................................................... 35 
11.5 
OWNERSHIP OF THE DATA ....................................................................................................... 39 
12 
STATISTICAL ASPECTS ................................................................................................... 39 
12.1 
DESCRIPTION OF STATISTICAL METHODS TO BE USED INCLUDING THE TIMETABLE FOR THE PLANNED 
INTERIM ANALYSES ................................................................................................................. 39 
12.2 
CALCULATION HYPOTHESES FOR THE NUMBER OF SUBJECTS REQUIRED AND THE RESULT .......... 44 
12.3 
IN THE CASE OF A COMPARATIVE RANDOMISED RESEARCH, THE CALCULATION IS BASED ON A 
HYPOTHESIS OF A DIFFERENCE BETWEEN THE TWO GROUPS IN THE PRIMARY ASSESSMENT CRITERIA, 
AND IS A FUNCTION OF THE ALPHA AND BETA RISKS ACCEPTED, OF THE UNI-OR BILATERAL 
FORMULATION AND OF THE VARIANCE (IN THE CASE OF A QUANTITATIVE VARIABLE). ................... 43 
13 
QUALITY CONTROL AND ASSURANCE ......................................................................... 45 
13.1 
GENERAL ORGANISATION ........................................................................................................ 45 
13.2 
QUALITY CONTROL.................................................................................................................. 46 
13.3 
CASE REPORT FORM .............................................................................................................. 46 
13.4 
MANAGEMENT OF NON-COMPLIANCES ...................................................................................... 52 
13.5 
AUDITS/INSPECTIONS .............................................................................................................. 47 
13.6 
PRIMARY INVESTIGATOR'S COMMITMENT TO ASSUME RESPONSIBILITY ....................................... 47 
13.7 
PHARMACIST'S COMMITMENT TO ASSUME RESPONSIBILITY ........................................................ 48 
14 
ETHICAL AND LEGAL CONSIDERATIONS ..................................................................... 48 
14.1 
METHODS FOR OBTAINING INFORMATION AND CONSENT FROM RESEARCH PARTICIPANTS ............ 48 
14.2 
SUBJECT PROHIBITED FROM PARTICIPATING IN ANOTHER RESEARCH OR AN EXCLUSION PERIOD 
ANTICIPATED AFTER THE RESEARCH, IF APPLICABLE ................................................................. 48 
14.3 
LEGAL OBLIGATIONS ............................................................................................................... 48 
14.4 
REGISTRATION ON THE NATIONAL REGISTER OF SUBJECTS PARTICIPATING IN BIOMEDICAL RESEARCH 
RELATING TO THE PRODUCTS LISTED IN ARTICLE L. 5311-1 OF THE FRENCH PUBLIC HEALTH CODE
 ............................................................................................................................................. 49 
14.5 
REQUEST FOR AUTHORISATION TO ANSM ................................................................................. 49 
14.6 
COMMITMENT TO COMPLIACE WITH THE MR 001”MÉTHODOLOGIE DE REFERENCE ..................... 49 
14.7 
STANDARD FOR AUTHORISATION TO ANSM ............................................................................. 49 
14.8 
MODIFICATIONS TO THE RESEARCH ......................................................................................... 49 
14.9 
FINAL RESEACH REPORT ......................................................................................................... 49 
15 
FUNDING AND INSURANCE ............................................................................................. 49 
15.1 
FUNDING SOURCE ................................................................................................................... 49 
15.2 
INSURANCE ............................................................................................................................ 50 
16 
PUBLICATION RULES ....................................................................................................... 50 
16.1 
MENTION OF THE AFFILIATION OF LE GHU PARIS PSYCHIATRIE ET NEUROSCIENCES FOR PROJECTS 
SPONSORED OR MANAGED BY LE GHU PARIS PSYCHIATRIE ET NEUROSCIENCES ...................... 50 
16.2 
MENTION OF THE LE GHU PARIS PSYCHIATRIE ET NEUROSCIENCES MANAGER (DRCI) IN THE 
ACKNOWLEDGEMENTS OF THE TEXT ........................................................................................ 50 
16.3 
MENTION OF THE FINANCIER IN THE ACKNOWLEDGEMENTS OF THE TEXT .................................... 50 

 
 
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17 
BIBLIOGRAPHY ................................................................................................................. 56 
18 
LIST OF ADDENDA ............................................................................................................ 52 
18.1 
LIST OF INVESTIGATORS .......................................................................................................... 52 
18.2 
FORM FOR REPORTING SERIOUS ADVERSE EVENTS ................................................................. 52 
18.3 
QUESTIONNAIRE OR SCALE ..................................................................................................... 52 
 
 
 

 
 
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1 
SUMMARY 
Full title 
Is adding Cilostazol to nimodipine improving neurological outcome 
of patients with Aneurysmal Subarachnoid 
Hemorrhage? A randomized, double blind, placebo-controlled trial 
Acronym 
CASH 
Coordinating 
Investigator  
Caroline SCHIMPF Service d’Anesthésie Réanimation GHU Paris 
Psychiatrie et Neurosciences Tel.01 45 65 74 13 Courriel : 
c.schimpf@ghu-paris.fr 
Sponsor 
Le GHU Paris Psychiatrie et Neurosciences 
Scientific justification 
Delayed neuronal damage following aneurysmal subarachnoid 
hemorrhage (SAH) is a major cause of mortality and handicap; it 
implies 
multiple 
factors 
involving 
delayed 
ischemia 
and 
vasospasm. To date, nimodipine is the only preventive drug known 
to improve neurological outcome of these patients and is the only 
pharmacological preventive treatment that is recommended by the 
European stroke organization. Many other drugs have been tested, 
with contradictory results; among them, cilostazol, a selective 
inhibitor of phosphodiesterase 3 (PDE 3), seems to get the more 
promising results on long-term handicap prevention. Its action 
includes an antiplatelet effect by increasing the availability of cyclic 
adenosine monophosphate (cAMP) via its inhibition of PDE 3 which 
degrades cAMP, thus increasing activity of protein kinase A (PKA) 
which leads to a downstream effect. In addition, an increase in NO 
production was observed in human aortic endothelial cells by a 
PKA-mediated activation of endothelial NO synthase (eNOS), 
leading to vasodilatation. The antithrombotic effect of cilostazol 
coupled with this vasodilatory action makes it a widely used 
treatment for arteriosclerosis obliterans, intermittent claudication, 
and prevention of a second ischemic stroke. Its action might go 
beyond this effect for preventing delayed cerebral ischemia 
following SAH; experimental studies show that cilostazol also 
attenuates cortical spreading and hydrocephalus, protects vascular 
endothelial cells and inhibits the proliferation of vascular smooth 
muscle cells. These numerous neuroprotective effects might 
explain its effectiveness, with a significative decrease (up to 50%) 
of unfavorable outcome rate, as described in several meta-analysis 
while other drugs or interventions focusing on vasospasm seem to 
fail in improving long-term functional outcome despite improving 
short-term radiographic results. Unfortunately, all cilostazol studies 
were conducted in Japan, with patients treated using fasudil, a 
potent 
Rho-kinase 
inhibitor, 
rather 
than 
nimodipine, 
as 
recommended by local guideline. Our hypothesis is that adding 
cilostazol to nimodipine in the acute phase of aneurysmal SAH 
improves long-term neurological outcome. 
Primary objective and 
assessment criterion  
Our hypothesis is that adding cilostazol to nimodipine for 14 days 
following 
aneurysmal 
subarachnoid 
hemorrhage 
improves 
neurological outcome 6-months after SAH, assessed by the 
modified Rankin scale. 
Secondary objectives 
and 
assessment 
criteria 
Functional status evaluated at 6 months:  
- MOCA score  
- Return to work  
- Activities of Daily Living  

 
 
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- Instrumental Activities of Daily Living  
In-hospital morbi-mortality:  
- Length of Intensive Care Unit stay  
- Length of hospital stay  
- 28-day mortality  
Strong clinical and radiological predictive events of functional 
status:  
- Delayed cerebral ischemia, defined as the occurrence of focal 
neurological impairment or a decrease of at least 2 points on the 
Glasgow Coma Scale, which is not apparent immediately after 
aneurysm occlusion and not attributable to other causes.  
- Short term evolution of Angiographically defined vasospasm, 
defined as a reduction of calibre of proximal cerebral vessels seen 
on either CT-, MR- or catheter angiography  
- Cerebral infarcts, defined by a diagnosis of cerebral infarction 
performed by a CT or MR scan within 6 weeks, or on the latest CT 
or MRI scan made before death within 6 weeks, or at autopsy, not 
present on the CT or MRI scan between 24 and 48 h after early 
aneurysm occlusion and not 
Experimental design 
Multicentre, 
double-blinded, 
randomised, 
placebo-controlled, 
parallel-group superiority trial using an adaptive group-sequential 
design 
Population involved 
Adult patients admitted to an intensive care unit with subarachnoid 
hemorrhage caused by a ruptured cerebral aneurysm 
Inclusion criteria 
- Ruptured cerebral aneurysm occurring in the last 96 hours  
- Aneurysm successfully secured by surgical clipping or 
endovascular coiling 
- Consent of the patient or, if not possible, of a family member 
(emergency clause) 
- Registration in a national health care system 
Non-inclusion criteria 
- Precritical modified Rankin Scale (mRS) > 2  
- Non-aneurysmal SAH  
- Delayed > 96h admission after first symptoms of SAH 
- Coma defined by GCS of 3-5 with untreatable aneurysm will be  
excluded”  
-  
- Known allergy to cilostazol  
- Pregnancy  
- Pre-existing major hepatic, renal, pulmonary or cardiac disease  
- Concomitant use of one other anti-platelet and/or anticoagulant 
agent 
- Tutelage or guardianship 
Treatment 
being 
tested 
Cilostazol 
- Phase III 
- Oral or enteral by gastric tube administration 
- Starting in the first 96 hours of occurrence of SAH 
- 100mg twice daily 
- For 14 days 
Benchmark treatment   
Other 
procedures 
added by the research 
Standard of care of SAH patients is not modified by the study, may 
vary across centres but must include:  
- Enteral or IV nimodipine administration  
- Vasospasm / DCI monitoring and treatment  

 
 
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- Radiological assessment of brain damage by cerebral TDM or 
MRI at day 10-21 
 
Face to face interview at 6 months by a clinical research assistant 
from the investigating centre or coordinating investigating centre. 
 
Risks added by the 
research 
1.1 
Level C  
 
Summary 
of 
the 
known 
and 
foreseeable 
benefits 
and 
risks 
for 
the 
research participants 
The incidence rate of SAH is high, 10 per 100.000 among which 
85% are caused by a ruptured aneurysm: neurological deterioration 
is frequent during the ICU stay and is mainly due to delayed 
cerebral ischemia. The most recent meta-analysis showed that 
cilostazol significantly reduced poor outcome patients with SAH, 
with an Odds ratio of 0.52 [0.37 – 0.74] for unfavourable outcome 
(16). Our trial aims to confirm that a 14 days administration of 100 
mg twice a day of cilostazol will reduce by 30% long-term disability 
and cognitive impairment of aneurysmal SAH. If so, our trial might 
dramatically change the therapeutic management of aneurysmal 
SAH, as nimodipine did long time ago. Collective benefit is also 
expected, including the reduction of the length of hospital stay and 
need for rehabilitation. 
The study protocol will not interfere with other preventive or curative 
treatment of DCI and vasospasm, which will be kept to the 
discretion of the physician in charge. 
 
Major secondary effects of cilostazol are arrhythmia, abnormal 
bleeding, and allergy (frequency not reported). Most frequent 
adverse reactions are headache (up to 34%), palpitation (up to 
10%), and diarrhoea (up to 19%). These side effects are however 
reported in patients taking cilostazol as a long-term therapy. In 
previous trial on DCI prevention in SAH, 14 days administration of 
cilostazol appeared safe since no difference in major adverse 
events rate was observed between cilostazol and control groups. 
Practical procedure 
Patients will be included within the first 96 hours after admission 
and randomly assigned to one of the following groups: the 
cilostazol group, who will receive cilostazol 100mg orally or by 
enteral tube two times a day for 14 days, or the control group, who 
will receive a placebo. This treatment should be started within the 
first 96 hours after hemorrhage. 
Number of subjects 
chosen 
630 patients 
Research period 
 
Inclusion: 42 months 
Participation: 6 months 
Total: 49 months  
Number of inclusions 
expected per centre 
and per month 
1.9 patients per centre and per month 
Statistical analysis 
2 interim analysis planned 
Funding source 
PHRC 
Data 
Safety 
Monitoring 
Board 
anticipated 
Yes 

 
 
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2 
SCIENTIFIC JUSTIFICATION FOR THE RESEARCH 
2.1 
Hypothesis for the research  
 
Delayed vasospasm of major cerebral arteries is considered the main cause of delayed 
cerebral ischemia (DCI) in patients with subarachnoid hemorrhage (SAH)1. However, reduction 
of angiographic vasospasm using intra-arterial vasodilatation or drugs such as clazosentan 
has not been shown to reduce DCI or long-term disability2,3. These findings have broader the 
conceptual view of DCI, by including to vasospasm other factors, such as microthrombosis, 
microvascular constriction, spreading depolarization and spreading ischemia. 
Cilostazol is a selective inhibitor of phosphodiesterase 3 (PDE 3) and antiplatelet agent. 
Its physiological properties combine multiple mechanisms, including inhibition of both cyclic 
adenosine monophosphate (cAMP) and upregulation of endothelial NO synthesis.  
In previous clinical studies, it has been shown to reduce DCI by increasing the release of nitric 
oxide levels from endothelial cells; by inhibiting the vascular smooth muscle proliferation; by 
suppressing the adhesion molecule expression on vascular membrane; and by inhibiting the 
platelet-derived growth factor production4-6. 
Our hypothesis is that the preventive administration of cilostazol improves long-term 
neurological outcome of patients presenting with SAH, by reducing DCI rate through these 
aforementionned multiple mechanisms. 
 
2.2 
Description of knowledge relating to the pathology in question  
The incidence rate of subarachnoid hemorrhage (SAH) is approximately 10 per 100,000, 
among which 85% are caused by a ruptured aneurysm. It accounts for about 5% of all strokes. 
The mortality rate is 30-50% and delayed cerebral ischemia (DCI) affects about 30% of SAH 
survivors; the risk of DCI is correlated with the Fisher radiologic score and the World Federation 
of Neurosurgeons score and contributes to poor outcome, long-term disability and cognitive 
impairment7 The DCI mainly occurs between the 4th and the 10th day after SAH8,9 . 
To date, only administration of nimodipine, as a preventive strategy of DCI, has been 
shown to improve long-term neurological outcome10,11 . It is therefore widely used, although its 
efficacy is limited. Its mechanisms of action, as a calcium antagonist, include vasodilatation 
and antifibronolytic effect. 
Data on curative treatment of vasospasm and DCI shows weak evidence and 
contradictory results, whether pharmacological or intra-arterial interventions. Therefore, 
management of these complications differs among intensive care units. However, it always 
includes close monitoring of clinical deterioration; when it occurs, hypertension therapy, intra-
arterial dilatation and sometimes adjuvant therapy such as milrinone are used. If sedation is 
needed making clinical examination not reliable, monitoring of vasospasm with using 
transcranial Dopplers, electroencephalographic recordings and perfusion CTscans are 
performed, although the clinical consequences of a radiological vasospasm, when found, is 
often a matter of debate. 
Despite advances in treatment and care protocols, the mortality and morbidity rate of 
SAH remains high: up to 40% patients of these adults are unable to return to work and even 
fewer are able to return to their previous occupations because of neurological impairment1  
Therefore, prevention of DCI remains a major priority. 
 
2.3 
Summary of relevant pre-clinical experiments and clinical trials 
To date, four randomized controlled trials have assessed cilostazol in improving long-
term outcome of adult patients with SAH.  

 
 
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In 2011, Suzuki and al. published the first prospective placebo-controlled study evaluating 
cilostazol in SAH patients12 . A hundred patients were enrolled: although cilostazol did not 
significantly decrease the incidence of symptomatic vasospasm (37.3% in the control vs. 
22.4% in the cilostazol group, p = 0.18) and cerebral infarction (27.5% in control vs. 10.2% in 
the cilostazol, p = 0.09). However, the modified Rankin scale at discharge was significantly 
improved: 2.6 in controls vs. 1.5 in the cilostazol group, p = 0.041.  
Senbokuya and al. published a second randomized controlled trial in 201313 . In this 
study, data from 109 patients were analysed. Symptomatic vasospasm, angiographic 
vasospasm and incidence of new cerebral infarctions were significantly lower in the cilostazol 
group, respectively 13 vs. 40% p=0.0021, 50 vs. 77% p=0.006, and 11 vs. 29% p=0.03. 
Nevertheless, no statistically significant difference was found regarding mRS at 1, 3 and 6 
months but the cilostazol group tended to have better outcomes defined as an mRS 0-2; at 6 
months, 88.9% patients and 74.5% had a good outcome in the cilostazol and placebo groups, 
respectively p=0.08. The number of adverse events in both groups was similar. 
Matsuda et al. in 2016 included 148 patients in a randomized placebo-controlled study14 . 
Occurrence of symptomatic vasospasm was significantly less frequent in the cilostazol group: 
10.8 vs. 24.3%, p = 0.031, as well as the proportion of patients with poor outcome: 5.4 vs. 
17.6%, p = 0.011. Multiple logistic analyses showed that cilostazol administration was an 
independently associated with reduced poor outcome: OR 0.221, 95% CI 0.054–0.903, p = 
0.035. 
Sugimoto et al. in 2018 included 50 cases that were randomly assigned to cilostazol 
(n=23) and placebo (n=27) groups15 . Among the 48 analysed patients, those from the 
cilostazol group tended to have a better clinical outcome than those from the control group, 
according to the  eGOS at 6 months after SAH (74% versus 56%). This difference was however 
not statistically significant (odds ratio 1.437, 95% CI 0.376 to 5.483, P=0.596). 
These four studies were selected in recent meta-analysis16 , which concluded that 
cilostazol might be beneficial in SAH patients with an OR of 0.52 [0.37 – 0.74] for unfavourable 
outcome.  
 
It must be noted that that all these studies have been conducted in Japan, have 
included relatively small cohorts and have administered the fasudil, a potent Rho-kinase 
inhibitor, instead of the nimodipine. 
Our study will be therefore the first to evaluate whether cilostazol, in addition to nimodipine, 
decreases the rate of long-term disability in a large cohort of patients with aneurysmal SAH. 
 
2.4 
Description of the population to be studied and justification for the choice of 
participants  
Adult patients admitted to an intensive care unit (ICU) for an aneurysmal SAH occurred 
within the last 96 hours. 
We decided to include only aneurismal SAH because of the low incidence rate of DCI 
and bad outcome in non-aneurismal SAH. Moreover, we decided to include all stages and 
grades of SAH. Indeed, previous studies suggested that it might be beneficial for all patients 
regardless of their severity. 
Since we hypothesised that cilostazol will improve the outcome by preventing treatment 
DCI, it should be started at the early phase of SAH before the risk period for DCI, which begins 
at day 4.  
 
2.5 
Identification and description of the experimental medication or medications 
 
Cilostazol is a selective inhibitor of phosphodiesterase 3 (PDE 3) and antiplatelet agent. 
It is available in a tablet form and can be administered orally or through a gastric tube after 
being crushed.  

 
 
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2.6 
Description and justification of the dosage, administration method, administration 
design and treatment period. 
 
Patients will be included within the first 96 hours after SAH onset and randomly 
assigned to either cilostazol or placebo group. The dose of cilostazol will be 100mg twice a 
day for 14 days,.  
The dosage of cilostazol is similar to the one tested in the four previous trial that documented 
benefit12-15.  
 
Pharmacokinetics justification 
We reviewed ten human studies that have directly quantified cilostazol’s pharmacokinetics 
under varied dosing and design protocols. In healthy volunteers—primarily Korean subjects—
one study reported an AUC of 12,100 ± 4,880 ng·h/ml , while Cmax values ranged from 283.7 
to 1,623.9 mg/ml over doses from 25 to 300 mg . Elimination half-life consistently approximated 
11 hours , and Tmax varied between 2.4 and 4 hours ; one report estimated apparent clearance 
(CL/F) at 12.8 l/h.17–26 
Genetic analyses indicate that CYP3A5 and CYP2C19 variants significantly affect clearance 
and half-life, whereas ABCB1 appears to have no effect, overall the variance explained by 
polymorphism was 7% underlining a relevant but limited effect of genetics on cilostazol 
pharmacokinetics. A study in subjects aged 50 and older found no significant influence of age 
or gender . Investigations of drug interactions reveal no notable pharmacokinetic change when 
cilostazol is co-administered with probucol, but co-administration with simvastatin increases 
simvastatin AUC by 64% and its active metabolite by 31%. The drug will be delivered in oral 
form if patient is able to swallow the tablet. If not, tablets will be crushed by the nurse in charge 
of the patient, and given by oral or enteral route through feeding tube if required. Administration 
of crushed tablet will be standardized at specific timing in each center. In case a patient can 
eat a meal, the delay between administration and meal will be of 30 minutes minimum 
 
Based on the available data in healthy human studies, the most common cilostazol dose 
across studies was 100 mg, administered either as a single dose or twice daily. Several studies 
used this dosing regimen: 
• 
Single 100 mg doses were used in studies by Choi and Kim17,18 
• 
Multiple 100 mg twice-daily doses were used in studies19,20  
• 
Some studies also investigated 50 mg doses21,22  or a range of doses. One dose-
escalation study examined doses from 25 mg to 300 mg23 . 
The most common route of administration was oral, and for multiple-dose studies, the typical 
regimen was twice daily (BID) dosing19,24. 
 
Dosage in SAH 
 
More specifically on subarachnoid hemorrhage, the dose of 100 mg twice daily for 14 
days was chosen based on previous clinical trials evaluating cilostazol in subarachnoid 
hemorrhage (SAH) patients. Specifically: 
• 
Previous randomized controlled trials (RCTs) in Japan, such as those by Suzuki et 
al. (2011), Senbokuya et al. (2013), Matsuda et al. (2016), and Sugimoto et al. 

 
 
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(2018), have used this dosage with documented efficacy in reducing delayed 
cerebral ischemia (DCI) and improving neurological outcomes. 
• 
Pharmacokinetically, cilostazol is a phosphodiesterase 3 inhibitor that increases 
cyclic AMP (cAMP), leading to vasodilation and antiplatelet effects. These 
mechanisms contribute to its potential protective role in preventing secondary 
ischemia after SAH. 
• 
Preclinical studies have shown that cilostazol inhibits vascular smooth muscle 
proliferation, enhances nitric oxide (NO) synthesis, and reduces 
microthrombosis, mechanisms that are relevant in SAH pathophysiology. 
Thus, the 100 mg BID dose was selected to match the dosage in prior successful studies while 
ensuring a favorable safety profile, for which adverse events are depicted in the section 
10. 
 
 
2.7 
Summary of the known and foreseeable benefits and risks for the research 
participants 
The incidence rate of SAH is high, 10 per 100.000 among which 85% are caused by a 
ruptured aneurysm: neurological deterioration is frequent during the ICU stay and is mainly 
due to delayed cerebral ischemia. The most recent meta-analysis showed that cilostazol 
significantly reduced poor outcome patients with SAH, with an Odds ratio of 0.52 [0.37 – 0.74] 
for unfavourable outcome16. Our trial aims to confirm that a 14 days administration of 100 mg 
twice a day of cilostazol will reduce by 30% long-term disability and cognitive impairment of 
aneurysmal SAH. If so, our trial might dramatically change the therapeutic management of 
aneurysmal SAH, as nimodipine did long time ago. Collective benefit is also expected, 
including the reduction of the length of hospital stay and need for rehabilitation. 
The study protocol will not interfere with other preventive or curative treatment of DCI 
and vasospasm, which will be kept to the discretion of the physician in charge. 
 
Major secondary effects of cilostazol are arrhythmia, abnormal bleeding, and allergy 
(frequency not reported). Most frequent adverse reactions are headache (up to 34%), 
palpitation (up to 10%), and diarrhoea (up to 19%). These side effects are however reported 
in patients taking cilostazol as a long-term therapy. In previous trial on DCI prevention in SAH, 
14 days administration of cilostazol appeared safe since no difference in major adverse events 
rate was observed between cilostazol and control groups.  
3 
OBJECTIVES  
3.1 
Primary objective 
Our main objective is to show that 100mg twice a day of cilostazol over 14 days improves the 
modified Rankin scale at 6-months in aneurysmal SAH treated with nimodipine, against 
placebo (Appendix 1) 
3.2 
Secondary objectives 
Secondary objectives are the functional status assessed at 6 months:  
-SubArachnoid Hemorrhage Outcome Tool (SAHOT) Score (Appendix 2) 
-MOCA score (Appendix 3) 
-Return to work  
-Activities of Daily Living (Appendix 4) 
-Instrumental Activities of Daily Living (Appendix 5) 

 
 
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And In-hospital morbi-mortality:  
-Length of ICU stay  
-Length of hospital stay 
-28-day mortality  
 
We will also assess the effects of cilostazol on the occurrence of: 
-Delayed cerebral ischemia, defined as the occurrence of focal neurological impairment 
or a decrease of at least 2 points on the Glasgow Coma Scale, which does not occur 
immediately after aneurysm occlusion and which is not ascribable to other causes.  
-Cerebral artery vasospasm, defined as a reduction of the diameter of the proximal 
cerebral vessels seen on either CT-, MR- or catheter angiography  
-Cerebral infarcts, detected on the CT scan or MRI performed with 6 weeks, (or on the 
latest CT scan or MRI performed before death within 6 weeks, or at autopsy), but not present 
on the earlier CT or MRI scan performed between 24 and 48 h after early aneurysm occlusion 
and not ascribable to other causes  
 
4 
WE WILL ALSO MONITOR THE OCCURRENCE OF CILOSTAZOL-RELATED 
ADVERSE AND SERIOUS ADVERSE EVENT.PLAN FOR THE RESEARCH 
4.1 
Concise description of the primary and secondary assessment criteria 
4.1.1 Primary assessment criterion 
Modified Rankin Scale (mRS) assessed at 6 months in a structured face-to-face 
interview. Favorable outcome is defined by an mRS score 0 to 2, and unfavorable outcome by 
a mRS from 3 to 6. (Appendix 1) 
 
The Modified Rankin scale allows to score the functional state. It is the most widely used 
outcome in patients with SAH17. It can be passed in a face-to-face interview by physicians, 
physical therapists, a research assistant or research nurses. Its overall agreement is 81% 
(κ=0.74, κw=0.91) when structured interview is used and displays an excellent repeatability.  
4.1.2 Secondary assessment criteria 
 
The main pitfall of the modified Rankin Scale is the overrating of patients that develop cognitive 
impairment. We thus chose to assess separately cognitive impairment with using specific 
scales, including the MOCA, ADL and IADL. The SAHOT (SAH-outcome tool) will be finally 
assessed, as it has been recently developed and validated but not yet commonly used as the 
mRS18 .   
 
1. SAHOT score (Appendix 2) 
2. MOCA score at 6 months (Appendix 3) 
3. Return to work at 6 months  
4. Activities of Daily Living (ADL) at 6 months (Appendix 4) 
5. Instrumental Activities of Daily Living (IADL) at 6 months (Appendix 5) 
 
Other generic morbidity criterion will be used. 
6. Length of Intensive Care Unit (ICU) stay  
7. Length of hospital stay  
8. 28-day mortality  
 

 
 
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We will also assess the occurrence of cerebral vasospasm, delayed cerebral ischemia 
and new cerebral infarction as they represent potential confounding factors. Of note cerebral 
vasospasm diagnosis will be left to the discretion of physician as the strategy to undergo 
arterial MR/CT scan or DSA differs widely across centres but interpretation of these exams will 
be requested to be standardized in all participating centres. As aforementioned, New cerebral 
infarcts will be considered when detected on the CT scan or MRI performed with 6 weeks, (or 
on the latest CT scan or MRI performed before death within 6 weeks, or at autopsy), but not 
present on the earlier CT or MRI scan performed between 24 and 48 h after early aneurysm 
occlusion and not ascribable to other causes 
 
9. Occurrence of DCI during the ICU stay  
 
DCI will be defined as the occurrence of  
 
• 
Focal neurological deficit (such as hemiparesis, aphasia, apraxia, hemianopia, or 
neglect), or 
• 
Decrease of at least 2 points on the Glasgow Coma Scale (either on the total score or 
on one of its components [eye, motor on either side, verbal]).  
 
➢ for at least 1 hour,  
➢ not apparent immediately after aneurysm occlusion, and  
➢ cannot be attributed to other causes by means of clinical assessment, CT or MRI 
scanning of the brain, and appropriate laboratory studies 
 
10. Occurrence of cerebral vasospasm on a brain imaging on digitally substracted 
angiography (DSA) or Magnetic resonance/computed tomography angiogram 
(MR/CTA) performed upon clinical signs of delayed cerebral ischemia or severe 
impairment of cerebral blood velocity in transcranial doppler 
 
Cerebral Vasospasm diagnosis will be defined upon DSA or MR/CTA. 
On angiograms in DSA or MR/CTA, the severity of vasospasm will be considered none 
or mild if there is a less 33% decrease in arterial diameter on angiography, moderate if there 
is a 34% to 66% decrease, or severe if there is at least a 67% decrease. 
 
DSA or MR/CTA will be performed when: 
o There are signs of delayed cerebral ischemia as described above. 
o There is a severe impairment of cerebral blood flow velocity assessed with help of 
transcranial doppler (tCD), as defined below. tCD will be performed at the discretion of 
the physicians in charge. tCD is a non-invasive radiation free exam that can be used 
at bedside. Its repetition allows a better detection of vasospasm and is routinely 
performed. Cerebral vasospasm severity will be evaluated according to this scale: 
 
Degree of cerebral blood 
velocity alteration 
Mean flow velocity 
(cm/s) 
Lindegaard ratio 
Mild 
120-149 
3-6 
Moderate 
150-199 
3-6 
Severe 
>200 
>6 
 
 
11. Occurrence of new cerebral infarcts  

 
 
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New cerebral infarct is considered when detected on the CT scan or MRI performed 
with 6 weeks, (or on the latest CT scan or MRI performed before death within 6 weeks, or at 
autopsy), but not present on the earlier CT or MRI scan performed between 24 and 48 h after 
early aneurysm occlusion and not ascribable to other causes such as surgical clipping or 
endovascular treatment. Hypodensities on CT imaging resulting from ventricular catheter or 
intraparenchymal hematoma should not be considered cerebral infarctions secondary to DCI. 
 
12. Occurrence of cilostazol-related major adverse events, including: arrythmia, abnormal 
bleeding and allergy.  
 
13. Occurrence of cilostazol-related minor adverse events include: tachycardia, fever, 
fainting, nausea, vomiting and stomach pain. 
 
4.2 
Description of research methodology  
4.2.1 Experimental plan 
 
CASH is a multicentre, double-blinded, randomised, placebo-controlled, parallel-group 
superiority trial in adult, using an adaptive group-sequential design, to demonstrate that 
cilostazol plus nimodipine is safe and superior to placebo plus nimodipine for improving 
modified Ranking Score (mRS) at six months. 
Two interim analyses for futility and efficacy are planned. 
 
4.2.2 Investigational centers 
 
Several selected centers will participate in the study. The list of Investigators will be managed 
separately from the study protocol and Competent Authorities will be kept informed of the 
update of the list. 
Patients will be recruited during hospitalization. 
 
4.2.3 Identification of the subjects 
During or at the end of the research, the data transmitted to the sponsor by the 
investigators (or any other specialized contributors) will be rendered non-identified. Under no 
circumstances should the names or addresses of the participants be made clear. The 
sponsor will ensure that each person who is subject to the research has given his or her 
consent for access to individual data concerning him or her that are strictly necessary for the 
research. 
For this research, the subjects will be identified as follows:  
Centre No. (3 numerical positions) - Selection order No. of the person in the centre (4 
numerical positions) - surname initial - first name initial 
This reference is unique and will be retained for the entire research period. 
4.2.4 Randomisation  
 
After screening for inclusion and non-inclusion criteria, and obtaining consent, patients 
will be randomized (1:1 ratio) to cilostazol or placebo groups by logging onto a randomization 
website using a pre-prepared randomization list, balanced by randomly variable block 
size. Randomization will be stratified by centre, age (<50 years; >=50 and <=75Years; >75 
years); and severity (Fisher grade from I to III; Fisher grade IV) 

 
 
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Randomisation will occur in an online data entry platform, guaranteeing the 
concealment of the experimental arm assigned to the doctor performing the inclusion and 
randomisation of the patient. 
The randomisation code will be disclosed once recruitment is completed. 
 
4.2.5 Blinding methods and provisions put in place to maintain 
blindness 
The physician investigator in each participating ICU will, after the patient fulfils the 
inclusion criteria and gives consent to participate in the CASH trial, use the online platform for 
data entry to randomize the patient, which in turn will allocate the participant to one of the two 
groups, from a pre-prepared randomization list. 
The randomization will be held in an online platform for data entry, and as such, ensures 
allocation concealment by not releasing the randomization code until the recruitment is 
completed. 
At the moment of randomisation in the e-CRF, visible to the investigator will only appear 
that "the patient was successfully randomised"; no other code will appear in the e-CRF. At the 
moment of randomisation, an email will inform the hospital pharmacy that a patient has been 
included and randomised; only the pharmacist will have access to the randomisation arm. 
Both trial participants, care providers, and outcome assessors will be blinded after the 
patients' assignment to one of the trial groups. The double blinding will be provided by the 
hospital pharmacy of promotor establishment using placebo pills similar to commercial pills. 
Nurses in charge will be blind to the study as well as the physician and research technician in 
charge of outcome assessment. 
In case of accidental loss of treatment, a form has to be completed with informations 
regarding the reason of the loss, the number of the patient and the number of days of treatment. 
The promotor will process the accident and will authorize or not the pursuit of the treatment. If 
the authorization is granted, the investigator site has to complete a form in the e-CRF for 
exceptional dispensing and will receive the code allowing the good dispensation according to 
the randomisation arm. 
4.2.6   Procedures for breaking the blind, if applicable  
 
Unblinding may be requested at any time and for any reason considered indispensable 
by the investigating physician, if a serious adverse event occur attributable to cilostazol, by 
calling the Délégation à la Recherche Clinique et à l'Innovation (Delegation for Clinical 
Research and Innovation) or the Pharmacy of Centre Hospitalier Sainte-Anne at the numbers 
given to each centre in the study protocol. 
In exceptional cases in which curative anticoagulation or antiaggregation is deemed 
necessary by the caring physicians, unblinding will be realized and a 10-hour wash out period 
will be advised in case of belonging to the cilostazol arm. 
 
5 
PROCEDURE FOR THE RESEARCH 
Consent will be obtained by an investigator from the patient, or from a relative if the patient 
is unable to consent, or using the emergency clause according to French Law if no relative 
could be contacted within 24 hours. If the patient is unable to consent, a pursuit consent will 
be sought as soon as the patient will be able to express its wills. 
 
Visits will be conducted daily throughout the stay in intensive care until D28. If the 
patient has been discharged from the ICU, a visit will be made at D28 to collect primary and 
secondary outcome data. An electronic case report file will be available to the research team 

 
 
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of each institution, on an online platform (Research Electronic Data Capture, REDCap, 
Vanderbilt University, Study data will be collected and managed using REDCap electronic data 
capture tools hosted at Centre Hospitalier Sainte-Anne. REDCap is a secure, web-based 
software platform designed to support data capture for research studies, providing 1) an 
intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; 4) procedures for data integration and interoperability with external 
sources.  
 
5.1 
Inclusion visit 
 
Inclusion visit will be conducted by the investigator of the participating centres. The inclusion 
visit will allow to check the inclusion and non-inclusion criteria. 
 
Inclusion criteria will be:  
• 
Age >18 yo  
• 
Admission to an ICU 
• 
Aneurysmal SAH diagnosis made upon radiologic findings in CT scan or MRI  
• 
Clinical onset of SAH within the last 96 hours -  
• 
Aneurysm successfully secured by surgical clipping or endovascular coiling 
• 
Consent of the patient or, if not possible, from a proxy (emergency clause)  
• 
Registration in a national health care system 
 
Non-inclusion will be 
• 
Precritical modified Rankin Scale (mRS) > 2  
• 
Non-aneurysmal SAH  
• 
Delayed>96h admission after first symptoms of Aneurysmal SAH 
• 
Coma defined by GCS of 3-5 with untreatable aneurysm will be excluded 
• 
Known allergy to cilostazol  
• 
Pregnancy 
• 
Pre-existing major hepatic, renal, pulmonary or cardiac disease  
• 
Concomitant use of one other anti-platelet and/or anticoagulant agent  
• 
SAH diagnosed on LP with no evidence of blood on CT. 
• 
Tutelage or guardianship 
 
During the inclusion visit, the following characteristics will be collected: 
 
Demographic data: 
• 
Age 
• 
Sex 
• 
Medical history (High blood pressure, tobacco use, drugs use, cocaine use, n° Unit of 
alcohol/d consumed, diabetes and other comorbidities according to the Charlson score 
(see Appendix 6) 
SAH history 
• 
Date of onset 
• 
Initial loss of consciousness 
• 
Onset seizure 
• 
Meningeal syndrome 
• 
Sudden headache 

 
 
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Severity at hospital admission 
• 
WFNS score 
• 
GCS 
• 
Motor deficit 
• 
Pupillary status 
 
Radiologic findings on first CT:  
• 
Localisation of aneurism having bled (anterior, posterior circulation) 
• 
Multiple aneurism 
• 
Largest aneurism size (mm) 
• 
Hijdra score,  
• 
Fisher score 
• 
Intraventricular haemorrhage 
• 
Intraparenchymal hematoma 
• 
Acute hydrocephalus 
• 
Area of previous ischemia  
• 
Area of recent ischemia 
• 
Fisher scale (Appendix 9) 
 
Specific complications up to inclusion: 
• 
High intracranial pressure (ICP) when measured (normal ICP will be considered if not 
monitored) > 20mmHg 
• 
Radiological findings at inclusion or >6hours after aneurism treatment 
o Area of recent ischemia 
o Recurrent bleeding 
o Acute hydrocephalus 
 
Treatment up to inclusion: 
• 
Time from symptoms to treatment (hours) 
• 
Endovascular therapy 
• 
Surgical clipping 
• 
Hemicraniectomy 
• 
Hematoma resection 
• 
Lobectomy 
• 
Mechanical ventilation 
• 
Catecholamine administration 
• 
Continuous sedation 
• 
Extraventricular drainage 
• 
Therapy intensity level (Annexe 5) 
 
Clinical examination at the time of inclusion: 
• 
SAH severity according to WFNS,  
• 
GCS score, 
• 
Neurological focal sign at admission 
• 
Anisocoria 
 

 
 
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5.2 
Follow-up Visits  
 
Follow up visits will be performed daily from day 1 to day 28. One Brain imaging will be realized 
24/48 hours after the aneurism treatment and one between day 28 and 45 after randomization. 
Transcranial doppler, MR CTA or DSA results will be collected when realized. 
 
Day 1 to day 28 
Vital status 
Compliance to treatment  
Experimental Treatment administration will be collected daily  
 
Safety follow up 
• 
Any major Cilostazol-related adverse event will be assessed: 
o Arrythmia from auricular origin 
o Arrythmia from ventricular origin 
o Abnormal bleeding 
o Allergy 
• 
Other minor Cilostazol-related adverse events: 
o Tachycardia, 
o Fever 
o Fainting 
o Nausea 
o Vomiting 
o Stomach pain 
 
Cerebral vasospasm 
• 
Blood flow velocity increase on TCD 
• 
Cerebral vasospasm diagnosed upon MR/CTA or DSA and its severity 
(mild/moderate/severe) 
 
Delayed cerebral ischemia 
• 
New focal deficit 
• 
Glasgow point decrease 
• 
No other cause  
 
Treatment in the last 24 hours 
• 
Continuous sedation 
• 
Mechanical ventilation 
• 
Extraventricular drain 
• 
Therapy Intensity Level (TIP) for Raised ICP treatment (See Appendix 7) 
• 
Hypertension therapy 
• 
Vasopressors (epinephrine/norepinephrine/dobutamine) 
• 
Milrinone administration 
• 
Endovascular treatment (Balloon therapy or vasodilatator administration) 
• 
Other treatment 
• 
At ICU discharge, the modified Rankin scale will be evaluated by a blinded research 
technician in case of lost to follow up. 
 

 
 
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5.3 
End of research visit at 6 months 
The end of research visit will be made at 6 months or when the patient terminates the 
study.  
Primary outcome 
The physician, physical therapist, research assistant or research nurse will collect 
blindly the mRS if the patient is alive. A face-to-face structured interview will be held during 
which the modified Rankin scale will be assessed (Appendix 1, 17).  
 
Functional and cognitive status will be collected during the patient’s consultation at 6 months, 
with using:  
-SAHOT Score 
-MOCA score  
-Return to work  
-Activities of Daily Living  
-Instrumental Activities of Daily Living  
 
The in-hospital morbity indicators will be collected, including:  
-Length of Intensive Care Unit stay  
-Length of hospital stay 
 
The occurrence of cerebral vasospasm and DCI during ICU stay will be assessed, with 
collecting 
-Delayed cerebral ischemia, defined as the occurrence of focal neurological deficit or a 
decrease of at least 2 points on the Glasgow Coma Scale, which does not occur immediately 
after aneurysm occlusion and which is not ascribable to other causes.  
-Cerebral artery vasospasm, defined as a reduction of the diameter of the proximal 
cerebral artery on either CT-, MR- or catheter angiography  
-Cerebral infarcts, considered when detected on the CT scan or MRI performed with 6 
weeks, (or on the latest CT scan or MRI performed before death within 6 weeks, or at autopsy), 
but not present on the earlier CT or MRI scan performed between 24 and 48 h after early 
aneurysm occlusion and not ascribable to other causes 
5.4 
Expected length of participation and description of the chronology and duration 
of the research.  
Inclusion period 
42 months 
The included subjects’ length of participation, of 
which: 
• 
 Treatment period: 
2 weeks 
• 
 Follow-up period: 
6 months 
Total research period: 
49 months 
 
5.5 
Table or diagram summarising the chronology of the research 
 
 

 
 
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*A complete description of Clinical exam, paraclinical exam and tests are described 
specifically in each visit in section 5.1 to 5.3 
5.6 
       End of the trial 
 
The end of the reseach is defined as the date when the last visit of the last patient included in 
the study occurs. 
 
5.7 
Distinction between care and research 
 
TABLE: Distinction between procedures associated with "care" and procedures added 
because of the "research " 
 
Procedures 
and 
treatments carried out as 
part of the research  
Procedures and 
treatments associated 
with care 
Procedures and 
treatments added because 
of the research  
Treatments 
DCI and vasospasm 
preventive and curative 
treatments (must include 
nimodipine administration) 
Cilostazol or placebo 
administration during 14 
days 
Consultations 
Routine visits from the 
physician in charge 
Face to face interview at 6 
months 
Actions 
Inclusion visit 
Day 0-28 
End of research 6 months 
Informed consent  
x 
 
 
History 
x 
 
 
Clinical exam* 
X 
X 
X 
Para-clinical exam* 
X 
X 
X 
Medical procedures (ECG, etc.)  
 
 
 
Dispensation of treatments 
 
X 
 
Compliance 
X 
X 
X 
Adverse events 
 
X 
X 

 
 
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Blood samples 
Left to the discretion of the 
physician 
None 
Imaging, etc. 
Imaging (CT scan, 
MRI, TCD) left to the 
discretion of the 
physician 
All the imaging techniques 
evaluating secondary 
objectives are routinely 
realized 
 
5.8 
Termination rules 
5.8.1 Criteria and methods for prematurely terminating the 
research treatment 
 
5.8.1.1 
Different situations  
- Temporary termination of treatment, the investigator must document the reason for stopping 
and restarting the treatment in the subject's source file and the case report form (CRF) 
- Premature termination of treatment, but the subject is still included in the research, until the 
end of the subject's participation, the investigator must document the reason (if during the 
administration period, the patient get out of the ICU, the treatment will stop).   
- Premature termination of treatment and end of participation in the research.  
The investigator must: 
o Document the reason(s)  
o Collect the assessment criteria when participation in the research ends, if the 
subject agrees 
o In case of severe adverse event, subject will be closely monitored and followed. 
 
5.8.1.2 
Criteria and methods for the premature termination of the research 
 
- Any subject can withdraw from participating in the research at any time and for any reason.  
- The investigator can temporarily or permanently end a subject's participation in the research 
for any reason that affects the subject's safety or which would be in the subject's best 
interests. 
- In case of loss of follow-up, the investigator must try to contact the subject by any means 
possible in order to know at least if the patient is still alive, and report it in the patient’s file. 
 
If a subject leaves the research prematurely, data relating to the subject can be used unless 
an objection was recorded when the subject signed the consent form.  
 
If consent is withdrawn, no data about the subject may be used unless the subject states in 
writing that he/she does not object. In practice, the subject is excluded from the research. 
 
The case report form must list the various reasons for ending participation in the research: 
 Ineffective 
 Adverse reaction  
 Other medical problem 
 Subject's personal reasons 
 Explicit withdrawal of consent 
 
5.8.2 Follow-up of the subjects after the premature termination of 
treatment 
 

 
 
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Ending a subject's participation does not affect the normal management of the subject's illness 
in any way.  
If there are serious adverse events, the investigator must notify the sponsor and monitor the 
subject for a month following the premature termination of treatment. If treatment is stopped 
prematurely due to a serious adverse event, a serious adverse event notification form will be 
sent by fax (01 44 84 17 99) to the sponsor. The serious adverse event will be monitored until 
it is resolved. 
If a data and safety monitoring board (DSMB) has been created, this committee can specify 
and/or validate the monitoring methods. 
 
5.8.3 Methods for replacing subjects, if applicable 
 
A 10 % dropout rate of patients has been estimated and considered for the calculation of the 
number of subjects to be included. 
5.8.4 Terminating part or all of the research 
 
Le GHU Paris Psychiatrie et Neurosciences as sponsor or the Competent Authority (ANSM) 
can prematurely terminate all or part of the research, temporarily or permanently, upon the 
recommendation of a data and safety monitoring board in the following situations: 
- first of all, if suspected unexpected serious adverse reactions (SUSARs) are seen in an arm 
being treated or if there is a discrepancy in the serious adverse reactions between the 2 
arms being treated, and which require a reassessment of the benefit-risk ratio for the 
research [to be adapted]. 
- in the case of interim analysis: stopping treatment to demonstrate the efficacy of one of the 
arms being treated or on the other hand stopping due to futility 
- likewise, unexpected facts, new information about the product, in light of which the 
objectives of the research or of the clinical programme are unlikely to be achieved, can lead 
Le GHU Paris Psychiatrie et Neurosciences as sponsor or the Competent Authority (ANSM) 
to prematurely halt the research 
- Le GHU Paris Psychiatrie et Neurosciences as sponsor reserves the right to permanently 
suspend inclusions at any time if it appears that the inclusion objectives are not met. 
 
If the research is terminated prematurely, the decision and justification will be given by the 
sponsor, Le GHU Paris Psychiatrie et Neurosciences, to the Competent Authority (ANSM) and 
to the CPP within 15 days, along with recommendations from the Data and Safety Monitoring 
Board (if applicable).  
5.8.5 Screen failure 
A subject who signed a consent form, but did not meet the inclusion/exclusion criteria is 
classified as a screen failure. Subject number, demographics and reason for screen failure will 
be recorded. 
6 
ELIGIBILITY CRITERIA 
6.1 
Inclusion criteria  
- Adult patients admitted to an ICU with SAH related to a ruptured cerebral aneurysm occurring 
within the last 96 hours.  
 
- Aneurysm successfully secured by surgical clipping or endovascular coiling 
 

 
 
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- Consent of the patient or, if not possible, from a proxy (emergency clause). 
- Registration in a national health care system 
6.2 
Non-inclusion criteria   
- Precritical modified Rankin Scale (mRS) > 2  
- Nonaneurysmal SAH  
- Delayed >96h admission after first symptoms of SAH  
-  
- Coma defined by GCS of 3-5 with untreatable aneurysm will be excluded”  
- Known allergy to cilostazol  
- Pregnancy  
- Pre-existing major hepatic, renal, pulmonary or cardiac disease  
- Concomitant use of one other anti-platelet and/or anticoagulant agent 
- SAH diagnosed on Lumbar puncture with no evidence of blood on CT. 
- Tutelage or guardianship   
 
6.3 
Recruitment methods 
Patient’s screening for recruitment will take place in all the participating ICUs. 
An information form will be given to the patient or, if not possible, to a family member. 
 
 
 
Number of 
subjects 
Total number of subjects chosen 
630 
Number of centres 
9 
Inclusion period (months) 
42 
Number of subjects/centres 
79 
Number of subjects/centre/months 
1.9 
 
 
 
7 
TREATMENT ADMINISTERED TO RESEARCH PARTICIPANTS 
7.1 
Description of the experimental medication or medications 
7.1.1  Experimental medication 1 
 
Cilostazol 100mg tablets 
Packaging type : blisters 
Two times a day (every 12 hours) for 14 days, 28 tablets in total 
Storage: room temperature 
Shelf life: 3 years 

 
 
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Oral form if patient is able to swallow the tablet. If not, tablets will be crushed by the nurse in 
charge of the patient, and given by oral or enteral route through feeding tube if required. OF 
note administration of crushed tablet will be standardized at specific timing in each center. In 
case a patient can eat a meal, the delai between administration and meal will be of 30 minutes 
minimum 
 
Of note a market authorization (Autorisation de Mise sur le Marché) is available in France for 
cilostazol in chronic arteritis but no marketed anymore since 2010 in France. The GHU Paris 
Psychiatry and Neurosciences pharmacy will import cilostazol which is also marketed in 
Europe. The blinding as well as the creation of a placebo will be subcontracted to a competent 
GMP establishment. The logistic will be centralized by the pharmacy of the GHU Paris and the 
pharmaceutical circuit will be co-constructed between GHU Paris and pharmacies of the 
different investigator centres (storage and delivery). 
 
7.2 
Description of the non-experimental treatment or treatments (medications 
required for carrying out the research) 
7.2.1 Non-experimental medication 1 
As recommended by French and European guidelines, a preventive medication of DCI by 
nimodipine has to be administered during the ICU stay. The posology, route (IV or enteral) and 
length of treatment is left to the discretion of the caring physician. 
 
7.3 
Description of the traceability elements that accompany the experimental 
medication or medications 
Designated pharmacists responsible for the receipt, handling and dispensing of study drugs 
(active and placebo) will maintain study drug records during the study: details of how all phases 
of dispensing and withdrawal of unadministered drugs will be monitored and controlled, and 
the patient code/kit code correspondence will be described in the Pharmacy Manual to be 
established prior to the start of the study. 
 
The investigator must maintain an accurate record of the shipment, storage, and dispensing 
of the study drug in a drug accountability log. An accurate record including the date and amount 
of study drug dispensed to each subject must be available for inspection at any time. A study 
CRA assigned to monitor the investigational site will review these documents once study drug 
has been received by the investigational site. Study drug will be accounted for on an ongoing 
basis during the study. 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Investigator Manual. 
 
7.4 
Authorised and prohibited treatments (medicinal, non medicinal, surgical), 
including rescue medications 
Authorised treatments include every other preventive or curative treatments (medical or 
radiologic) for vasospasm and DCI, notably the use of milrinone, vasopressors for 
hypertension therapy (norepinephrine, dobutamine or epinephrine). 
Unauthorised treatments include other antiplatelet agent or curative anticoagulation treatment. 
In case of an anticoagulation or antiaggregant is deemed necessary by the caring physicians, 
unblinding of the randomization will be realized and a 10 hours washout period will be advised 
before anticoagulation start if possible if the patient was randomized to the cilostazol arm.  
Cilostazol dosage is modfied by CYP3A4 inhibitors (clarithromycin, erythromycin, 
diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit) or 

 
 
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CYP2C19 inhibitors (e.g., Chloramphenicol, Clomipramine, Delavirdine, Fluoxetine, 
Fluvoxamine, Gemfibrozil, Imipramine, Isoniazide, Lansoprazole, Miconazole), thus these 
drugs will be prohibited during the administration of cilostazol. In case of a proton pump 
inhibitor will be prescribed, pantoprazole will be preferred as it has a limited to no effect on  
CYP2C19 inhibitors19  If any of the other drug is prescribed, cilostazol dosing will be reduced 
to 50 mg BID to mitigate interaction risks. 
 
7.5 
  Methods for monitoring compliance with the treatment 
pharmacy visits will be planned, reporting: 
- 
Number of tablets administered 
- 
Number of tablets returned to the pharmacy 
 
8 
ASSESSMENT OF EFFICACY 
8.1 
Description of parameters for assessing efficacy 
Primary outcome 
It is the Modified Rankin score (mRS): 
It will be assessed at 6 months by physicians, physical therapists or research assistant 
or research nurses who would have been specifically trained to pass this score and who will 
be unaware of the trial-group assignments, during a face-to-face interview with patient. This 
structured interview will strengthen the interrater agreement (17)  
 
Methods for secondary assessment criterion collection 
 
At the 6 months interview and after collection of the mRS, one will proceed to the assessment 
of  
• 
The SAHOT score (Appendix 2). For facilitating its collection and reduce time of the 
consultation, the SAHOT questionnaire will be sent to the patients before the 6 months 
face-to-face interview. 
• 
MOCA score at 6 months (Appendix 3), which will be passed during the 6 months face-
to-face interview by the trained investigator. 
• 
Return to work at 6 months  
• 
Activities of Daily Living (ADL) at 6 months (Appendix 4) and Instrumental Activities of 
Daily Living (IADL) at 6 months (Appendix 5), which will be passed during the 6 months 
face-to-face interview by the trained investigator. 
 
Radiological endpoints will be collected daily during the ICU stay.  Delayed cerebral 
ischemia is defined in the section 4.1.2 Highest velocity in the mean cerebral artery evaluated 
in tCD will be collected when available. MR/CTA DSA vasospasm will be scored as mild, 
moderate or severe according to the narrowing of the cerebral arteries. 
 
 
 
 
8.2 
Anticipated methods and timetable for measuring, collecting and analysing the 
parameters for assessing efficacy 
Efficacy will be assessed with help of the mRS at 6 months, during a structured face-to-face 
interview of the patients which will involve one of the physicians, physical therapists, research 
assistants or research nurses of any participating centre. The organisation of the structured 

 
 
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face-to-face interview will be as similar as possible between centres. During this M6 visit, the 
secondary outcomes- related scores will also be collected: 
- 
SAHOT 
- 
MOCA score 
- 
Activities of Daily Living   
- 
Instrumental Activities of Daily Living   
- 
Return to work 
 
During hospital stay, other parameters evaluating efficacy will be prospectively collected and 
reported on the e-CRF: 
- 
Length of stay in the ICU 
- 
Length of hospital stay 
- 
28-day mortality 
9 
SPECIFIC RESEARCH COMMITTEES: 
Dénomination anglo-saxonne 
Dénomination française 
Caractéristiques 
Independent 
Data 
Monitoring 
Committee (IDMC) or Data Safety 
Monitoring Board 
 
Comité 
de 
surveillance 
indépendant (CSI) 
Membres indépendants 
de l’investigateur 
Steering Committee 
Comité de Pilotage 
Comité Scientifique 
Investigateurs, 
promoteur… 
Endpoint Adjudication Committee Comité 
de 
validation 
des 
évènements critiques 
Travail en aveugle 
 
Note: the Data Safety Monitoring Board (DSMB) is described in section 10. 
9.1 
Scientific committee 
• 
Members of the committee: Schimpf Caroline, Mazeraud Aurélien, Tarek 
Sharshar, Cinotti Raphael 
• 
Missions: define the objective, write the protocol, propose modifications to 
the protocol during the research 
• 
Operating methods: Distant meetings with prespecified agenda upon 
Coordinator Investigator request 
 
9.2 
Steering committee 
 
• 
Members of the committee: Caroline Schimpf, Isabelle Dufaure-Gare, 
Aurélien Mazeraud, Guillaume Turc, Khaoussou Sylla, Sylvain Leroy 

 
 
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• 
Missions: To propose guidelines during the course of the research, taking 
note of the recommendations of the independent monitoring committee, if 
any. The DRCI sponsor remains the decision maker. 
• 
Operating methods: Distant meetings with prespecified agenda upon 
promotor request 
 
9.3 
Endpoint Adjudication Committee  
✓ The adjudication committee's role is to analyze patient data in detail and conclude 
whether the event (endpoint) is present or not.The committee will therefore be made 
up of specialists in the pathology or endpoint of the trial. It is not necessarily 
independent of the trial, but the main thing is that it acts blindly. There is therefore a lot 
of preparatory work to provide the committee with anonymized and undated data. 
 
• 
Members of the committee: Ghazi Hmeydia, Mazeraud Aurélien, Caroline 
Schimpf, Camille Legouy 
• 
Missions: Secondary endpoints adjudication 
• 
Operating methods: Meetings when 25, 50, 75 and 100% of the patients are 
monitored. 
 
✓ Outcomes concerned : 
 
 
Secondary endpoints adjudication 
 
✓ Primacy of the opinion of the adjudication committee: 
 
The adjudicated outcome takes precedence over that of the investogator 
 
 
 
10 SAFETY ASSESSMENT - RISKS AND RESTRICTIONS ADDED BY THE 
RESEARCH 
10.1 Description of parameters for assessing safety  
SmPC will describe more detailed information on the known and anticipated risks and 
reasonably expected adverse events (AEs) of cilostazol. 
 
 
10.2 Anticipated methods and timetable for measuring, collecting and analysing the 
parameters for assessing safety  
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE, as provided in this protocol. During the study when 
there is a safety evaluation, the Investigator or site staff will be responsible for detecting, 
documenting and reporting AEs and SAEs as detailed in this Section of the protocol. 
 

 
 
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10.3 Procedures in place for recording and reporting adverse events 
Adverse events will be collected by physicians in charge on a daily basis, and reported through 
an e-CRF by investigators. They will be classified as mild, moderate or serious adverse events. 
10.3.1 Definitions (Regulation (EU) N° 536/2014 (REC) 
 
 
Adverse event Any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. 
 
• Adverse drug reaction  
Any response to a medicinal product which is noxious and unintended. 
 
• Serious adverse event  
Any untoward medical occurrence that at any dose results in death, is life-threatening, 
requires inpatient hospitalisation or prolongation of existing hospitalisation, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. 
 
• Unexpected adverse reaction  
An adverse reaction, the nature, severity or outcome of which is not consistent with the 
applicable product information: the summary of product characteristics (SmPC) for an 
authorised product or the investigator's brochure for an unauthorised investigational 
product. 
. 
 
According to the notice to sponsors of clinical trials for medications (ANSM):  
 
• New safety issue 
Any new information regarding safety: 
- that could significantly alter the assessment of the benefit-risk ratio for the experimental 
medication, or for the trial 
- or which could lead to the possibility of altering the administration of the experimental 
medication or altering the conduct of the trial 
 
Examples: 
a) any clinically significant increase in the frequency of an expected serious adverse reaction 
occurring  
b) suspected unexpected serious adverse reactions (SUSAR) occurring in patients who have 
finished the trial and about whom the sponsor is notified by the investigator, who also provides 
any follow-up reports 
c) any new fact relating to the conduct of the clinical trial or the development of the experimental 
medication, if the new fact is likely to affect participant safety  
Examples: 
- a serious adverse event likely to be related to the investigations and to the trial's 
diagnostic procedures and which could modify the conduct of this trial 
- a significant risk for the trial participants such as ineffectiveness of the experimental 
medication used in the trial in treating a life-threatening illness 
- significant safety results from a recently completed research carried out on animals 
(such as a carcinogenicity research) 
- the premature termination, or temporary interruption, of a trial conducted with the 
same experimental medication in another country, for safety reasons 

 
 
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- an unexpected serious adverse reaction associated with a non-experimental 
medication required for carrying out the trial, (e.g., challenge agents, rescue treatment) 
d) recommendations from the data safety monitoring board (DSMB), if applicable, if they are 
relevant to the safety of the participants 
e) any unexpected serious adverse reaction reported to the sponsor by another sponsor of a 
trial carried out in a different country but relating to the same medication 
 
10.3.2 The investigator’s roles  
 
10.3.2.1 Regulatory obligations of the investigator  
 
The investigator must notify the sponsor, immediately on the day when the investigator 
becomes aware, of all the serious adverse events, except those that are listed in the protocol 
(see. section 10.3.3.1) or in the investigator's brochure as not requiring immediate notification. 
 
These serious adverse events are recorded in the "adverse event" section of the case report 
form and the investigator must immediately notify the sponsor's Vigilance division (see 10.3.4). 
 
10.3.2.2 The investigator’s other roles 
 
The investigator must document the serious adverse event as thoroughly as possible and 
provide the medical diagnosis, if possible. 
 
The investigator assesses the severity of the adverse events by using an adverse events rating 
scale, attached to the protocol, by using general terms: 
- Mild: tolerated by the patient, does not interfere with daily activities 
- Moderate: sufficiently uncomfortable to affect daily activities 
- Serious: preventing daily activities 
 
The investigator assesses the causal relationship between the serious adverse events and the 
experimental medication(s) added by the research.  
10.3.3 Specific features of the protocol 
All serious and non-serious adverse events must be reported in the CRF. 
 
10.3.3.1 Serious adverse events that do not require the investigator to immediately notify 
the sponsor 
 
These serious adverse events are only recorded in the "adverse event" section of the case 
report form. 
 
• 
Normal and natural evolution of the pathology: 
 
Normal and natural evolution of aneurismal SAH is quite variable: 
- 
Even without initial neurological deficit, patients are closely monitored after securisation 
of the aneurism because of the risk of DCI, vasospasm, hydrocephalus, rebleeding, or 
any other unspecific complication. Patients in worse neurological condition can be 
initially intubated; the duration of mechanical ventilation dependst on the subsequent 
neurological improvement and intercurrent ICU complications. 
- 
Securisation of the aneurism can be performed with endovascular coiling or surgical 
clipping and lead to ischemic stroke 

 
 
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- 
Death occurs in approximately 30% of all cases. 
- 
DCI can occur from day 4 until the 21th day after SAH. This risk peaks about the 10th 
day. DCI can require hypertension therapy and infusion of vasopressor, adjunctive 
pharmacological treatment, notably milrinone, and endovascular treatment of 
vasospasm can be requested, but in a centre-dependant way 
- 
Other organ failure might occur as patients might require prolonged ventilatory support 
and developed ICU related complications, such as nosocomial infection. 
- 
Initial hydrocephalus can worsen the neurological status; it can occur from the first to 
15th day. It can require an external ventricular drain. The drain can often be weaned 
during hospitalisation but if not, internal ventricular drainage can be implanted. It is 
associated with a risk of nosocomial menigitis.  
- 
When the risk of DCI or other neurological complication is considered low enough, the 
patient is transferred to the ward until the patient is discharged from the hospital to 
either the patient’s home or a rehabilitation centre. 
 
• 
Adverse events likely to be associated with the treatments prescribed as part of 
the patient's care during the monitoring of the research  
 
10.3.3.2 Serious adverse events that require the investigator to immediately notify 
the sponsor 
 
The investigator must report all adverse events that meet one of the seriousness criteria below, 
except for events listed in section 10.3.3.1 as not requiring notification: 
1- Death 
2- Life threatening situation 
3- Requiring hospitalisation or prolonging hospitalisation 
4- Persistent or significant disability or incapacity 
5- Congenital abnormality or birth defect 
6- Or any other adverse event considered "medically significant" 
 
❖ For serious adverse events related to the experimental medication(s) and which are 
expected:  
- the -SmPC for the « cilostazol » speciality, found in (Appendix 5), should be consulted.  
 
❖ The serious adverse events associated with specific research procedures or exams, and 
which are expected, are:  
o Poorly tolerated auricular or ventricular arrythmia 
o Abnormal bleeding (requiring blood transfusion or not) 
o Allergy 
 
10.3.3.3 Other events that require the investigator to immediately notify the 
sponsor 
 
• 
Adverse events that are "not serious" but which are significant for the safety of 
participants  
• 
The following adverse event will be assessed: 
o Well tolerated arrythmia from auricular origin 
o Well tolerated arrythmia from ventricular origin 
o Tachycardia, 
o Fever 
o Fainting 

 
 
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o Nausea 
o Vomiting 
o Stomach pain 
• 
The investigator must notify the sponsor about these "nonserious" adverse events, in 
accordance with the same procedures and deadlines as serious adverse events (see 
section 10.3.4). These events can be considered "medically significant". 
 
• 
In utero exposure 
 
The sponsor must be notified immediately about any pregnancy during which the foetus 
(from the pre-embryonic stage up to birth) could have been exposed at a given time to an 
experimental medication, even if the pregnancy is not associated with an adverse event.  
 
Notification is required if the exposure involves: 
- the mother, 
- the father if the experimental medication is genotoxic.  
 
10.3.4 Procedures and deadlines for notifying the sponsor  
 
Notification of an SAE must initially be provided in a written report using the special form for 
reporting SAE. The report must be signed by the investigator. 
 
Each item in the form must be completed by the investigator so that the sponsor can carry out 
the appropriate analysis. 
 
This initial notification must be followed by one or more detailed follow-up report(s), in writing 
and signed, within a maximum of 8 days in the case of a fatal or life-threatening event and 
within 15 days for all other cases. 
 
Whenever possible, the investigator will provide the sponsor with any documents that may be 
useful (medical reports, laboratory test results, results of additional exams, etc.). These 
documents must be made anonymous. In addition, the documents must include the following: 
research acronym, number and initials of the subject, nature and date of the serious adverse 
event.  
 
Any adverse event will be monitored until fully resolved (stabilisation at a level considered 
acceptable by the investigator, or return to the previous state) even if the subject has left the 
trial. 
 
The initial notification, the SAE follow-up reports and all other documents must be sent to the 
sponsor via fax only to the Vigilance Division of the DRCI, fax No. 01 45 65 76 09. 
 
For studies using e-CRF: 
- the investigator completes the SAE notification form in the e-CRF, validates, prints and signs 
the form before sending it via fax. 
- if it is not possible to connect to the e-CRF, the investigator will complete, sign and send the 
SAE notification form found in the Investigator Worksheet. As soon as the connection is 
restored, the SAE notification form in the e-CRF must be duly completed.  
 
The investigator must comply with all requests from the sponsor for additional information.  

 
 
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For all questions relating to the notification of an adverse event, the DRCI can be contacted 
via email: drci@ghu-paris.fr 
 
The investigator must monitor the pregnant woman throughout her pregnancy or until the 
pregnancy is terminated, and must notify the sponsor of the outcome of the pregnancy, using 
this form. 
If the outcome of the pregnancy falls within the definition of a serious adverse event 
(miscarriage, pregnancy termination, foetal death, congenital abnormality, etc.), the 
investigator must follow the procedure for reporting SAE. 
If the exposure involves the father, the investigator must obtain the mother's permission before 
collecting information about the pregnancy. 
 
The initial pregnancy notification, the SAE follow-up reports and all other documents must be 
sent to the sponsor via fax only to the DRCI, fax No. 01 45 65 76 09. 
 
10.3.5 Period for notifying the sponsor 
 
The investigator must report all SAE that occur in research subjects:  
- after the date on which treatment with an experimental medication began 
- throughout the period during which the participant is monitored, as determined by the 
research  
- for up to 4 or more weeks after the participant stops treatment using the experimental 
medication 
- with no time limit, if the SAE is likely to be due to the experimental medication or to the 
research procedures (for example, serious reactions that could appear long after exposure 
to the medication, such as cancers or congenital abnormalities). 
10.3.6 The sponsor's roles 
 
The sponsor, represented by its DRCI, continuously assesses the safety of each experimental 
medication throughout the research.  
 
10.3.6.1  Analysis and declaration of serious adverse events 
 
The sponsor assesses: 
- 
the seriousness of all adverse events reported 
- 
the causal relationship of these events with each experimental medication and/or 
specific medical procedures/exams added by the research and with other possible 
treatments 
- 
the expected or unexpected nature of these adverse reactions 
 
All serious adverse events which the investigator and/or the sponsor believe could reasonably 
have a causal relationship with the experimental medication are considered as suspected 
adverse reactions.  
 
All suspected unexpected serious adverse reactions (SUSAR) are declared by the sponsor, 
within the legal time frame, to the Agence Française de Sécurité Sanitaire des Produits de 
Santé (ANSM, French Health Products Safety Agency) and to the relevant Comité de 
Protection des Personnes (CPP, ethical committee). 
 

 
 
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• 
The initial declaration must be made with no delay after the date on which the serious 
adverse event occurs in the case of death or of a life-threatening diagnosis. 
 
• 
The initial declaration must be made with no delay after the date on which the serious 
adverse event occurs in the case of other serious situations. 
 
• 
The follow-up declaration must be made with no delay. 
Any suspected unexpected serious adverse reaction must also be declared electronically in 
the Eudravigilance European database for adverse events due to medications, established by 
the European Medicines Agency (EMA). 
The sponsor must notify all relevant investigators about any data that could adversely affect 
the safety of the research subjects. 
 
Specific cases of serious adverse events of special interest: 
At the request of ANSM, the sponsor may be asked to declare serious adverse events of 
special interest, in accordance with the same procedures and deadlines as SUSARs.  
 
Specific case of double-blind trials 
As a general rule, the sponsor declares a suspected unexpected serious adverse reaction to 
the competent authorities and to the CPP after having broken the blind on the experimental 
medication. 
In exceptional situations, and if the ANSM grants permission when requested by the sponsor 
in the sponsor's clinical trial authorisation application, the methods for unblinding and for 
declaring suspected unexpected serious adverse reactions can be modified. These methods 
will then be defined in detail in the research protocol (see section 4.2.6). 
 
10.3.6.2  Analysis and declaration of other safety data 
 
This relates to any safety data or new fact that could significantly alter the assessment of the 
benefit-risk ratio for the experimental medication, or for the research, or which could lead to 
the possibility of altering the administration of the experimental medication or altering the 
conduct of the research. 
 
New facts must be declared to the competent authorities within 15 calendar days of the 
sponsor becoming aware. Additional relevant information must be sent within an additional 8 
days after the 15-day deadline. 
 
10.3.6.3 Annual safety report 
 
Once a year for the duration of the clinical trial, the sponsor must draw up an annual safety 
report (Development Safety Update Report - DSUR) which includes, in particular: 
- an analysis of the safety of the research subjects 
- a description of the patients included in the trial (demographic characteristics, etc.) 
- a line listing of suspected serious adverse reactions that occurred during the period covered 
by the report 
- a cumulative summary tabulation of serious adverse events that have occurred since the start 
of the research 
 
The report must be delivered no later than 60 days after the anniversary of the date on which 
the ANSM authorised the trial. 
 

 
 
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10.3.7 Data Safety Monitoring Board  
 
The Data and Safety Monitoring Board (DSMB) can be established by the sponsor. Its primary 
mission is to serve as a committee for monitoring safety data. It can have other missions, such 
as monitoring efficacy data (especially if the protocol includes interim analyses).  
The DSMB is mentioned in Article L. 1123-7 of the French Public Health Code.  
 
The sponsor is responsible for justifying the creation or absence of a supervisory committee 
to the Competent Authority (ANSM) and to the CPP. 
 
A DSMB will be convened for this biomedical research. The members of the DSMB will be 
named after the research starts. During the first meeting of the DSMB, a chairman will be 
appointed and the members will determine their operating methods and the meeting schedule. 
All missions as well as the precise operating methods of the DSMB will be described in the 
DSMB’s charter for the research. 
 
 
General information about the DSMB 
The DSMB makes recommendations to the sponsor about the continuation, modification or 
termination of the research upon interim analysis. The recommendations that the DSMB can 
make are: 
- to continue the research with no modifications 
- to continue the research with a modification to the protocol and/or to the monitoring of 
subjects 
- to temporarily halt inclusions 
- to permanently terminate the research in light of: 
o safety data: serious adverse reactions 
o efficacy data: proven futility or efficacy 
 
The DSMB is appointed by the sponsor and is made up of at least 3 people with no connection 
to the research, including at least one clinician specialising in the pathology being studied and 
one specialist in the medication being studied (or a pharmacologist/pharmacovigilance 
specialist), and possibly a methodologist/biostatistician, particularly in the case of interim 
analysis.  
 
The DSMB has a consultative role in advising the sponsor on safety issues such as tolerance 
and re-assessment of the benefit-risk ratio during the research.  
 
The DSMB must hold its preliminary meeting before the first inclusions of the first subject and 
ideally before the protocol is submitted to the competent authority and the CPP. The 
committee's agenda will be as follows:  
 
Definition of the DSMB's missions:  
- Validation of the research methodology:  
The proposed methodology for the clinical trial will be validated by the DSMB so that it does 
not jeopardise the safety of subjects, in particular relating to the inclusion and randomization 
methods.  
- Validation of tolerance monitoring methods:  
o nature of the evaluated parameters 
o frequency of the evaluations, consultation schedule 
 
- Validation of termination criteria:  
o criteria for terminating a subject's participation for tolerance reasons 

 
 
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o criteria for the temporary or permanent termination of the research (leading to the 
establishment of certain recommendations ("stopping rules")) 
 
- Modification of the protocol and recommendations: 
In light of the analysis of tolerance data for the research, the DSMB can, when applicable:  
propose substantial modifications in order to modify certain data, in particular relating to the 
protocol (inclusion and non-inclusion criteria, monitoring, additional exams, etc.). Likewise the 
DSMB can issue any recommendations it deems useful in order to best ensure the safety of 
the research subjects and to maintain a favourable benefit-risk balance throughout the 
research.  
 
Definition of the DSMB's operating methods: 
- meeting types (open session, then closed sessions) and schedule 
- desired methods and format of SAE notification from the sponsor to the DSMB 
The DSMB appoints its chairman at the first meeting. 
 
The sponsor retains decision-making authority. When applicable, the sponsor delivers its 
decision, with justification, and DSMB reports to the Competent Authority (ANSM) and the 
CPP. 
 
11 DATA MANAGEMENT 
11.1 Data collection methods 
Study data will be collected and managed using REDCap electronic data capture tools hosted 
at Centre Hospitalier Sainte-Anne. REDCap is a secure, web-based software platform 
designed to support data capture for research studies, providing 1) an intuitive interface for 
validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; 
4) procedures for data integration and interoperability with external sources.  
 
 
11.2 Identification of data collected directly in the CRFs and that will be considered as 
source data  
Patients will be identified through their initials, number center and randomization number. 
11.3 Right to access source data and documents  
11.3.1 Access to data 
In accordance with GCPs: 
- the sponsor is responsible for obtaining the permission of all parties involved in the research 
to guarantee direct access to all locations where the research will be carried out, to the source 
data, to the source documents and the reports, with the goal of quality control and audit by the 
sponsor 
- the investigators will make available to those in charge of monitoring, quality control and audit 
relating to the biomedical research the documents and personal data strictly necessary for 
these controls, in accordance with the legislative and regulatory provisions in force (Articles 
L.1121-3 and R.5121-13 of the French Public Health Code) 
 

 
 
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11.3.2 Source documents 
Source documents are defined as any original document or object that can prove the existence 
or accuracy of a piece of information or a fact recorded during the research. These documents 
will be kept for 15 years by the investigator or by the hospital in the case of a hospital medical 
file. Electronic Health record and Radiological reports will be kept by the investigators of each 
centre 
11.3.3 Data confidentiality 
Those responsible for biomedical research quality control (Article L.1121-3 of the French 
Public Health Code) will take all necessary precautions to ensure the confidentiality of 
information about the experimental medications, the research, the research subjects and in 
particular the identity of the subjects and the results obtained. 
These individuals, as well as the investigators themselves, are subject to professional secrecy 
(in accordance with the conditions set out in Articles 226-13 and 226-14 of the Penal Code). 
During or after the biomedical research, the data collected about the research subjects and 
sent to the sponsor by the investigators (or any other specialised parties) will be made non-
identifying. 
Under no circumstances should the names and addresses of the subjects involved be shown.  
The sponsor will ensure that each research subject has given permission in writing for access 
to personal information about him or her which is strictly necessary for the quality control of 
the research.  
11.3.4 Data security 
11.3.4.1 Measures Implemented Upstream: 
• 
Presence of a full-time Data Protection Officer (DPO) and Chief Information Security 
Officer (CISO) internally; 
• 
Raising awareness among employees about personal data protection (both in paper and 
digital formats), privacy, and cybersecurity; 
• 
Confidentiality and IT tool usage charters in place and signed by all employees, 
partners, and service providers; 
• 
Established Information Security Policy (PSSI); 
• 
Regular IT system audits and remediation of any identified risks; 
• 
Cybersecurity aspects :  
o Securing remote access via VPN + MFA, 
o TLS access for web applications, 
o Pseudonymization and encryption of data, 
o Segmentation (separating web sections from databases), 
o Logical access control through ID+Password authentication, with deactivation 
of unused accounts after 3 months, 
o Account blocking after multiple failed login attempts, 
o Securing IT communication channels (firewall, traffic monitoring probes), 
o Inventory (CMDB) and hardware redundancy, 
o Access granted per project, 
o Securing operations: daily backup policy for VMs and servers, PSSI; 
o Data archiving policy preventing any subsequent modification or extraction; 
o Strict compliance with the principle of data minimization; 
o Protection against malware (XDR solution, DMZ servers, and traffic control). 
    

 
 
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11.3.4.2 Measures to Be Implemented in Case of a Data Security    
Breach to Mitigate Possible Negative Effects: 
• 
Restoration of lost data via daily backups in case of loss of availability or unintended 
modification; 
• 
Set of measures preventing the reuse of data in case of theft, interception, etc. 
(encryption through VPN + MFA + TLS access for web applications); 
• 
Personal data breach management policy (notification of the incident to the CNIL, 
general and personal communication to affected individuals, etc.). 
 
11.4 Data processing and storage of documents and data  
11.4.1 Identification of the manager and the location(s) for data 
processing 
The data management will be realized in the DRCI of GHU Paris Psychiatrie et Neurosciences 
with Didier André and the statistical analysis will be done by Isabelle Dufaure-Gare. 
11.4.2 Data entry 
Data entry will be carried out on electronic media via a web browser connecting to the REDCAP 
server hosted at GHU Paris Psychiatrie et Neurosciences center 
 
11.4.3 Data processing (CNIL, the French Data Protection Authority) 
in France 
This research falls under the "Méthodologie de référence" (MR-001) according to the 
provisions of Article 54, paragraph 5 of modified Law No. 78-17 of 6 January 1978 relating to 
information technology, data files and privacy. This change was approved in a decision made 
on 5 January 2006. Le GHU Paris Psychiatrie et Neurosciences, the research sponsor, has 
signed a commitment to comply with this " Méthodologie de référence "  
 
The processing of personal data for this research falls under the scope of the provisions of 
Articles 53 to 61 of the Law of 6 January 1978 relating to information technology, data files and 
privacy, modified by Law No. 0204-801 of 6 August 2004.  
 
11.4.4 Archival 
Specific documents for biomedical research relating to a medication for human use will be 
archived by the investigator and the sponsor for a period of 15 years after the end of the 
research.  
This indexed archival includes, in particular:  
- A sealed envelope containing the original copies of all information sheets and consent 
forms signed for all individuals at the centre that participated in the research for the 
investigator 
- A copy of all the information notes and consent forms signed for all subjects at the centre 
that participated in the research for the sponsor 
- "Research" binders for the Investigator and the sponsor, including: 
• 
the successive versions of the protocol (identified by the version no. and date), and the 
appendices 
• 
the ANSM authorisations and CPP favourable opinions 

 
 
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• 
letters of correspondence 
• 
the inclusion list or register 
• 
the appendices specific to the research 
• 
the final research report 
- The data collection documents 
 
11.5 Ownership of the data  
Le GHU Paris Psychiatrie et Neurosciences is the owner of the data, which cannot be used or 
disclosed to a third party without its prior approval. 
12 STATISTICAL ASPECTS  
12.1 Description of statistical methods to be used including the timetable for the 
planned interim analyses 
CASH is a multicentre, double-blinded, randomised, placebo-controlled, parallel-group 
superiority trial in adult, using an adaptive group-sequential design, to demonstrate that 
cilostazol plus nimodipine is safe and superior to nimodipine alone will improve modified 
Ranking Score (mRS) at six months. 
Two interim analyses for futility and efficacy are planned. 
Populations 
For the statistical analysis, the following populations are defined: 
Population 
Description  
Intent-To-Treat 
(ITT) 
Population  
The ITT population will include all randomised participants. ITT 
participants will be analysed according to the randomised 
treatment, regardless of the actual treatment received. All 
efficacy analyses will be performed on the ITT population. 
Per 
Protocol 
(PP) 
Population  
The PP population will include all participants in the ITT with at 
least 80% of doses received to define adherence to treatment. 
The PP population will be used for supportive analyses of 
efficacy measures.  
Safety Population (SP) 
The SP will include all randomised participants who received at 
least one treatment (active or placebo). The SP will be analysed 
according to the actual treatment received. This population will 
be used for safety analyses. 
  
 Description of the statistical methods, including the timing of planned interim analyses 
  
The statistical analysis plan (SAP) will be developed and finalised before the database is 
locked.  
Below is a description of the planned statistical analysis. Further details will be presented in 
the statistical analysis plan (SAP). 
All statistical analyses will be performed with SPSS version 26 or RStudio. For analyses 
performed with RStudio, the script used will be provided. 
The baseline is defined as the last evaluation performed before the start of the study treatment, 
day 1 (V1). 
All data collected after the start of the study treatment are defined as post-baseline. 

 
 
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Baseline characteristics will be summarised by the treatment group. The mean and standard 
deviation (SD) or median and interquartile range (IQR) for skewed variables will be 
summarised for continuous measures. 
The proportion in each category will describe categorical variables.  
In addition, the 95% confidence interval (CI) will also be calculated as indicated. 
All categorical variables will be summarised by treatment with numbers and percentages of 
participants. 
All continuous variables, including changes from baseline, will be summarised by treatment 
with means, standard deviations or medians and interquartile range [IQR] for skewed 
variables.  
The following formula will be used, depending on how the post-basal endpoint is defined, for 
each scheduled visit and for each time point at which both baseline and post-basal values are 
available: 
− 
Change from baseline = post-baseline value - baseline value 
− 
Percentage change from baseline = (post-baseline value - baselinevalue)/basal 
value*100% 
− 
Ratio to baseline = post-baseline value / baseline value 
Primary objective 
 
The analysis of clinical effectiveness will be performed on the ITT population. 
For the assessment of the primary objective, the percentage of patients who responded to 
treatment per experimental arm will be evaluated. Specifically, treatment will be considered 
effective when mRS at six months is ≤2.  
Therefore, the treatment response variable will be dichotomised as follows 
0 if the mRS is > 2 (non-responder patient) 
1 if the the mRS value is ≤ 2 (responders). 
A logistic regression model adjusted by centre, age (continuous), and severity at inclusion, 
considering the dichotomised value of the mRS (<=2, >2) as the response variable, and will be 
used. Consequently, the efficacy of the experimental treatment will be expressed as an 
adjusted Odds Ratio, and the 95% confidence interval and NNT index will be provided. 
Sensibility analysis 
The described analysis for the assessment of clinical efficacy will be repeated in the per-
protocol population and after the replacement of missing data of mRS at six months, on the 
one hand, according to a "worst case scenario" logic and on the other hand, using multiple 
imputations. 
 
Secondary efficacy analyses 
 Secondary analyses of clinical effectiveness will be performed on the ITT population. Analyses 
on per protocol population may be carried out. 
A logistic regression model adjusted by centre, age (continuous) and severity at inclusion will 
be used considering the dichotomised mRS value at six months (≤1 versus >1). 
The time-to-event variables will be analysed using the Cox proportional hazards model, 
including randomisation arm, age (as a continuous variable), severity at inclusion, and centre 
as model terms. The hazard ratio between the arms will be presented with the 95% CI and p-
value of the model. Kaplan-Meier curves will be presented by the arm for each appropriate 
endpoint. 
For the primary objective, both overall and by subgroups, the following statistics will be 
provided: effect size, confidence intervals, number needed to treat and absolute risk reduction 
as appropriate. 
All tests will be two-sided with a unilateral significance level of 0.025% adjusted for the interim 
analysis. 
 
Subgroup analyses 
 

 
 
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 Subgroup analyses will be performed to assess the consistency of the treatment effect 
between subgroups without multiplicity adjustment. The following subgroups will be assessed 
for the primary endpoint: 
− Fisher grade I to III versus IV 
− Age: <50 years; >=50 and <=70 years; >70 years  
The treatment effect for the total population and subgroups will be represented using forest 
plot graphs. 
For HR and OR in subgroup analyses, the significance of the interaction will be tested using 
the method proposed by Altman & Bland 2003. 
 
Treatment of missing data 
 
For the analysis of the primary endpoint, in the event of study exit prior to evaluation of the 
primary endpoint (6 months), the last recorded mRS value will be used (LOCF method, mRS 
at ICU discharge) patients will be considered as non responders if no mRS are recorded. 
For all other variables, in case of a significant proportion of missing data (>10% of subjects), a 
sensitivity analysis using multiple conditional imputation techniques by chained equations 
(MICE) will be performed, according to a conservative principle, using the mean severity at 
inclusion as the central position parameter and an estimate of the intra-patient variability in the 
placebo group as the dispersion parameter. Sensitivity analysis based on imputed data will be 
considered secondary. 
Further details on the treatment of missing data will be provided in the SAP. 
 
 
12.2 Definition of Estimands in the CASH Trial 
We define two primary estimands corresponding to the intention-to-treat (ITT) and per-protocol 
(PP) analyses, as well as an additional estimand incorporating neurological mortality. 
 
12.2.1 Primary Estimand – Intention-to-Treat (ITT) Analysis 
This estimand aims to assess the effect of cilostazol added to nimodipine on the modified 
Rankin Scale (mRS) at 6 months, considering all randomized patients, regardless of 
intercurrent events. 
• 
Target Population: All randomized patients. 
• 
Variable of Interest: mRS at 6 months, dichotomized as favorable outcome (mRS 0-2) 
vs. unfavorable outcome (mRS 3-6). 
• 
Handling of Intercurrent Events: 
o 
Early treatment discontinuation → "Treatment Policy" strategy: Patients remain 
in their randomized group, regardless of treatment adherence. 
o 
Death before 6 months → "Composite" strategy: 
▪ 
Neurological death → Counted as mRS=6. 
▪ 
Non-neurological death → Counted as mRS  in ITT analysis and a 
secondary analysis excluding these patients. 
o 
Loss to follow-up → "Composite" strategy: Last observation carried forward 
(LOCF) with multiple imputation as a sensitivity analysis. 
• 
Estimation Method: Logistic regression adjusted for age and initial severity (GCS 
grade) and centre. 
   Justification: This approach respects the ITT principle, ensures comparability between 
groups, and provides a realistic assessment of treatment effect. 
 

 
 
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12.2.2 Secondary Estimand – Per-Protocol (PP) Analysis 
This estimand aims to measure the effect of cilostazol only in patients who completed the 
treatment without interruption. 
• 
Target Population: Patients who received at least 80% of prescribed doses over the 
14-day treatment period. 
• 
Variable of Interest: mRS at 6 months (favorable vs. unfavorable) otherwise LOCF. 
• 
Handling of Intercurrent Events: 
o 
Early treatment discontinuation → "Principal Stratum" strategy: Only patients 
who completed treatment are analyzed. 
o 
Death before 6 months → "Composite" strategy (mRS=6 if neurological, 
secondary analysis excluding non-neurological deaths). 
• 
Estimation Method: Logistic regression model restricted to patients who completed 
treatment. 
   Justification: This analysis assesses the specific effect of cilostazol without treatment 
adherence interference. 
12.2.3 Additional Estimand – Impact of Mortality on the Analysis 
An additional estimand will be conducted to specifically evaluate the impact of neurological vs. 
non-neurological mortality: 
• 
Target Population: All randomized patients. 
• 
Variable of Interest: mRS at 6 months, considering: 
o 
mRS=6 for neurological deaths. 
o 
Exclusion of non-neurological deaths in a secondary analysis. 
   Justification: This analysis differentiates the specific effects of treatment on neurological 
mortality, which is crucial for interpreting the trial results. 
 
 

 
 
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12.3 Management of Intercurrent Events – Methodological Approach 
In this trial, we do not anticipate the use of rescue therapy, nor the occurrence of an intercurrent 
event directly related to the drug. The selected strategies reflect this specificity. 
 
Intercurrent Event 
Strategy 
for 
ITT 
Estimand 
Strategy 
for 
PP 
Estimand 
Justification 
Early 
treatment 
discontinuation 
"Treatment Policy" – 
Analyze 
in 
randomized group 
"Principal Stratum" 
– Exclude 
Maintains comparability in 
ITT, assesses adherence 
in PP. 
Neurological death "Composite" 
– 
Counted as mRS=6 
"Composite" 
– 
Counted as mRS=6 
Maintains 
comparability 
between groups. 
Non-neurological 
death 
"Composite" 
– 
Sensitivity analysis 
"Composite" 
– 
Sensitivity analysis 
Excludes deaths unrelated 
to the study in a secondary 
analysis. 
Loss to follow-up 
before 6 months 
"Composite" – LOCF + 
Multiple Imputation 
"Composite" 
– 
LOCF 
+ 
Multiple 
Imputation 
Reduces 
bias 
due 
to 
missing data. 
 
12.4 Statistical Analysis and Sensitivity Tests 
To ensure robust conclusions, we will apply multiple sensitivity analyses, in addition to ITT and 
PP analyses: 
1. Complete Case Analysis (excluding patients with missing data). 
2. Multiple Imputation of missing data to assess the impact of lost-to-follow-up cases. 
3. Scenario analysis excluding non-neurological deaths. 
 
Safety analysis 
  
For each patient and each type of toxicity described according to the CTCAE (V.5.0), the worst-
case category identified during treatment will be used for the descriptive analysis.  
Safety Measures  
Safety will be assessed using:  
• Incidence of treatment-related adverse events (TEAEs)  
• Incidence and severity of treatment-emergent adverse events (TEAEs)  
• Incidence of serious adverse events (SAEs)  
• Incidence of TEAEs and SAEs leading to discontinuation of study medication.  
• Changes in blood chemistry, hematology and coagulation parameter results  
• Changes in vital signs including temperature, pulse, respiratory rate, systolic and diastolic 
blood pressure  
• Changes in physical examination results  
• Changes in electrocardiogram (ECG) results  
These data will be described using lists and tables. 
 

 
 
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12.5 Sample size estimation   
To estimate the sample size, as no direct efficacy studies of cilostazol versus nimodipine or in 
combination with nimodipine versus placebo were available, a literature search was conducted 
to verify the possibility of performing a network meta-analysis that would allow an evaluation 
for indirect comparisons. 
Reference is made to a network meta-analysis [Dayyany, 2022] on prophylactic therapies for 
cerebral vasospasm secondary to SAH. 
The literature search of the referenced network meta-analysis stopped in February 2020; 
therefore, an update was performed on Medline according to the same strategies from 
February 2020 to December 2022.  
Therefore, for the network meta-analysis, trials using nimodipine, cilostazol or fasudil (the 
usual comparator or in combination with cilostazol) as prophylaxis in at least one arm of the 
study were selected. Concerning the outcome as per the main objective of the CASH study 
(mRS assessed at six months, where the favourable outcome is defined as the mRS score of 
0 to 2, and unfavourable outcome of 3 to 6) for the studies where the assessment was made 
using the GOSE, the results were converted as in Table 1. The meta-analysis was performed 
with MetaXL Version 5.3[1], a fixed-effects model was used, and the method for calculating 
the weighted average effect was the inverse of variance heterogeneity. The global 
heterogeneity of the model was assessed using the H inconsistency index [2]. 
The selected studies, the model description, and the results are reported in Appendix 8. 
 
 
Table 1. GOSE vs mRS conversion table 
Modified Rankin Scale (mRS) 
Glasgow Outcome Scale (GOS) 
0 - No symptoms. 
4 -  Moderate disability 
5 -  Low disability 
1 - No significant disability. Able to carry out all 
usual activities, despite some symptoms. 
2 - Slight disability. Able to look after own affairs 
without assistance, but unable to carry out all 
previous activities. 
3 - Moderate disability. Requires some help, but 
able to walk unassisted. 
1 -  Death 
2 -  Persistent vegetative state 
3 -  Severe disability 
4 - Moderately severe disability. Unable to attend 
to own bodily needs without assistance, and 
unable to walk unassisted. 
5 - Severe disability. Requires constant nursing 
care and attention, bedridden, incontinent. 
6 - Dead. 
  
A total of 9 studies with a cumulative number of 1732 patients were included in the network 
meta-analysis; the details are given in Table 2. 
  
Table 2: Trials selected for network meta-analysis and events for each study arm 
favourable outcome at the longest follow-up 
 
 
 
Active 
Control 
Active 
Control 
Study name 
Nb 
Case
s 
Non-
cases 
Nb 
Case
s 
Non-
cases 
Nimodipina 
Placebo 
Petruk,1988 
72 
28 
44 
82 
28 
54 
Nimodipina 
Placebo 
Pickard, 1989 
27
8 
223 
55 
276 
185 
91 

 
 
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Nimodipina 
Placebo 
Ohman, 1991 
10
4 
86 
18 
109 
86 
23 
Fasudil 
Placebo 
Shibuya, 1992 
13
6 
98 
38 
136 
95 
41 
Fasudil  
Nimodipin
a 
Zhao, 2006 
33 
27 
6 
34 
28 
6 
Fasudil plus 
Nimodipine 
Nimodipin
a 
Zhao_2, 2011 
55 
49 
6 
60 
48 
12 
Cilostazol plus Fasudil 
Fasudil 
Suzuki, 2011 
49 
39 
10 
51 
24 
27 
Cilostazol plus Fasudil 
Fasudil 
Sembukuya, 
2013 
54 
39 
15 
55 
36 
19 
Cilostazol 
Placebo 
Matsuda, 2016 
74 
60 
14 
74 
61 
13 
 
 
 
85
5 
649 
206 
877 
591 
286 
  
 
Figure 1. Network plot 
 
Figure 2. Forest plot 
  
The network meta-analysis versus nimodipine, where the outcome is the patient's status at at 
the longest follow-up, shows a non-inferiority of fasudil versus nimodipine (OR=0.720; 95% CI 
unilateral lower bound =0.050). 
The efficacy trend of the combination of fasudil plus cilostazol (OR= 2.25; 95% CI unilateral 
lower bound=0.705) and fasudil plus nimodipine (OR=2.04; 95% CI unilateral lower 
bound=0.840) compared to treatment with nimodipine alone appears to be sharper. 

 
 
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Considering that in both Japan and China, the standard prophylaxis after SAH is fasudil  or 
fasudil plus cilostazol, considering only trials evaluating combination versus monotherapy with 
nimodipine or fasudil, the greater efficacy of combination therapy is apparent. 
The results of the meta-analysis and the forest plot are reported below. A low heterogeneity 
was found (I2=0.45; p=0.16); therefore, the inverse variance heterogeneity model was applied 
(Doi, 2015) 
 
Study 
OR 
LCI 95% 
UCI 95% 
Weight 
(%) 
Zhao, 2011 (fasudil plus nimodipine vs nimodipine) 
2.042 
0.709 
5.880 
24.322 
Suzuki, 2011 (fasudil plus cilostazol vs fasudil) 
4.388 
1.809 
10.641 
34.665 
Sembukuya, 2013 (fasudil plus cilostazol vs 
fasudil) 
1.372 
0.608 
3.099 
41.013 
Pooled 
2.261 
1.108 
4.614 
100.000 
Statistics  
 
 
 
I-squared 
44.9 
 
 
 
Cochran's Q 
3.63 
 
 
 
Chi2, p 
0.163 
 
 
 
  
In light of the results obtained for the sample size estimation, an OR between the two arms of 
1.86 is assumed as a precaution. This assumption sets the proportion of patients who will 
obtain a favourable outcome in the control arm at 65% and the proportion of responders in the 
experimental arm at least 76%. These proportions may appear high, but it should be noted that 
the study does not include patients with early death and without surgery.  
The experimental design includes two intermediate analyses; a sequential group test and the 
O'Brian-Fleming Analog spending function for alpha and beta errors were used. 
Therefore set unilateral alpha at 0.025 and the power of the test (1-beta) at 0.80, 284 patients 
are needed per experimental arm; details are given in table 3 and figure 1.  
A drop-out rate of no more than 10% is expected so that the sample size will be 630 patients 
(315 per experimental arm). 
All estimates for the interim analyses are made without considering the inflation quota for drop-
out patients. Therefore this evaluation will be made at the planned number of patients who 
completed the study. Only the final analysis will bear any inflationary share of the sample. 
 
Table 3. Summary Report - ──────────────────────────────────────────────── 
  
Item 
Value 
Maximum Number of Stages (Design):  
3 
Current Stage:  
0 
Alternative Hypothesis:  
P1 - P2 < 0 (one-sided) 
Alpha Spending Function:  
O'Brien-Fleming Analog 
Beta Spending Function:  
O'Brien-Fleming Analog 
Futility Boundaries: 
Binding 
Target Alpha:  
0.025 
Alpha (from simulations):  
0.025 
P1:                                                                             0.65 
P2:                                                                             0.76 
N1 (if final stage reached):  
284 
N2 (if final stage reached):  
284 
Target Power:  
0.8 
Power (from simulations):  
0.8016 
Maximum Information:  
692.8 

 
 
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Information Report ────────────────────────────────────────────────────────── 
Maximum Information: 692.8519 
Alternative Hypothesis: P1 - P2 < 0 (one-sided) 
Alpha: 0.0250 
  
    
Stage 
Target 
information 
proportion 
Target 
sample size 
N1 
Target 
sample size 
N2 
P1 
P2 
1 
0.33 
95 
95 
0.65 
0.76 
2 
0.67 
189 
189 
0.65 
0.76 
3 
1.00 
284 
284 
0.65 
0.76 
       
Alpha Spending ──────────────────────────────────────────────────────────── 
Target Final Stage Alpha: 0.0250 
Spending Function: O'Brien-Fleming Analog 
Stage 
Information 
proportion 
Alpha spent this 
stage 
Cumulative 
alpha spent 
Percentage 
alpha spent at 
this stage 
Cumulative 
percentage 
1 
0.33 
0.0001 
0.0001 
0.4 
0.4 
2 
0.67 
0.0059 
0.0060 
23.8 
24.2 
3 
1.00 
0.0190 
0.0250 
75.8 
100.0 
Beta Spending for Futility ────────────────────────────────────────────────────── 
Target Cumulative Beta at Final Stage: 0.2000 
Spending Function for Futility: O'Brien-Fleming Analog 
Stage 
Information 
proportion 
Beta spent this 
stage 
Cumulative beta 
spent 
Percentage beta  
spent at this 
stage 
Cumulative 
percentage 
1 
0.33 
0.0264 
0.0264 
13.2 
13.2 
2 
0.67 
0.0901 
0.1165 
45.7 
58.3 
3 
1.00 
0.0835 
0.2000 
41.7 
100.0 
  
Boundary Probabilities for δ = -0.11 ─────────────────────────────────────────────── 
Number of Simulations: 100000 
Futility Boundaries: Binding 
After Efficacy Boundary Crossing: Hold Out 
After Binding Futility Boundary Crossing: Hold Out 
Alternative Hypothesis: P1 - P2 < 0 (one-sided) 
P1: 0.65 
P2: 0.76 
δ:   -0.11 
 
Stage 
 
N1 
 
N2 
Efficacy 
Futility 
Boundary 
Probability 
Boundary 
Probability 
1 
95 
95 
-3.7103 
0.0253 
0.2701 
0.0277 
2 
189 
189 
-2.5111 
0.4166 
-1.1224 
0.0885 
3 
284 
284 
-1.9308 
0.3597 
-1.9308 
0.0821 
  
Average N1: 226. 
Average N2: 226 
 

 
 
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Figure 1.  
12.6 Specify if subjects who leave the research prematurely will be replaced and in 
what proportion.  
 The primary outcome is assessed only one time 6 months after Day 0 (5 months and a half 
after last day of treatment) that could lead to patient’s loss to follow up. Nevertheless, SAH is 
a serious condition that requires a long and close patient’s monitoring. That will limit patient’s 
loss to follow up. The patients who leave study prematurally (for loss to follow up or death) 
won’t be replaced and will be considered as non responder patients in the main analysis of 
primary criterion. 
Some sensitivity analyses will be performed with complete cases only. 
Only, the particular circumstance of patient resignation will lead to exit patient of the primary 
analysis. A 10% rate of non evaluable patients is foreseen. 
12.7 Interim analysis 
The group-sequential study design provided two interim analyses when 190 and 378 patients 
completed the study. Figure 2 shows the stopping limits for the first interim analysis. 

 
 
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Figure 2. 
Three conditions will be possible: 
− 
Z-statistics in the favorable zone: stop for efficacy (z<=-3.710) 
− 
Z-statistics in the unfavorable zone: stop for futility (z>=0.270) 
− 
Z-statistics in the promising zone (z>-3.710 and <0.270) 
For the first interim analysis, only the conditions of futility and efficiency will be verified. A 
blinded statistical analysis of the study objective will be carried out and provided to the BMDC, 
which 
will 
advise 
on 
the 
continuation 
of 
the 
study. 
  
Figure 3 shows the stopping limits and the conditions for adaptive re-estimation of the sample 
size for the second interim analysis. 

 
 
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Figure 3. 
Three conditions will be possible: 
− 
Z-statistics in the favorable zone: stop for efficacy (z<=-2.511) 
− 
Z-statistics in the unfavorable zone: stop for futility (z>=-1.224) 
− 
Z-statistics in the promising zone (z>-2.511 and <-1.224) 
  
A blinded statistical analysis of the study objective will be carried out and provided to the IMDC, 
which will advise on the continuation of the study. 
Regarding the possibility of falling into the promising zone and considering clinically valid 
increase in patients with a favourable outcome compared to the control arm of at least 8 
percentage points (NNT@12), two simulations with 100,000 samples were performed.  
First, given the sample size (630 patients), the response rate in the control group was from 
0.68 to 0.70, and the response rate in the experimental group was fixed at 0.76; the boundary 
equal to -1.9308 as the O'Brian-Fleming expenditure function for the third interim analysis; 
solving then for beta (Table 4 shows the simulation plan). 
Table 4. Simulation Design for the last look 
Scenario 
Power 
N1 
N2 
Alpha 
Responders 
control 
Responders 
treatment 
1 
0.580 
315 
315 
0.025 
0.68 
0.76 
2 
0.477 
315 
315 
0.025 
0.69 
0.76 
2 
0.379 
315 
315 
0.025 
0.70 
0.76 
  

 
 
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The second simulation, with the same sample size and the same boundary, but in this case, 
varying the response rate in the experimental group (from 0.76 to 0.70) and response rate in 
the control group fixed at 0.65 (Table 3 shows the simulation plane) 
Table 4. Simulation Design for the last look 
Scenario 
Power 
N1 
N2 
Alpha 
Responders 
control 
Responders 
treatment 
1 
0.556 
315 
315 
0.025 
0.65 
0.73 
2 
0.656 
315 
315 
0.025 
0.65 
0.74 
2 
0.753 
315 
315 
0.025 
0.65 
0.75 
  
Should one of the scenarios occur, a new sample size estimate will be possible.  A conditional 
power analysis for the emerging z-value will be performed and provided to the IDMC. 
 
Independent Data Monitoring Committee (IDMC) 
  
An independent Data Monitoring Committee (IDMC) will closely review the safety data and 
efficacy of the interim analysis and provide recommendations for the continuation of the study. 
The IDMC will be composed of at least three members, of which at least one will be a specialist 
in the domain of neurology and at least one in the domain of reanimation and a methodologist. 
The members of the IDMC will be appointed before the protocol is submitted to the ethics 
committee for final approbation. 
13 QUALITY CONTROL AND ASSURANCE  
Each biomedical research project managed by Le GHU Paris Psychiatrie et 
Neurosciences is ranked from A to D according to the projected risk incurred by research 
subjects using the classification of biomedical research sponsored by Le GHU Paris 
Psychiatrie et Neurosciences 
 
13.1 General organisation 
The sponsor must be responsible for the safety and respect of those subjects who have 
agreed to participate in the research. The sponsor must implement a quality assurance system 
to best monitor the conduct of the research in the investigation centres. 
 
For this purpose, the sponsor shall delegate Clinical Research Associates (CRA) 
whose primary role is to carry out regular follow-up visits at the research locations, after having 
carried out initial visits. 
The objectives of monitoring the research, as defined in the French Good Clinical 
Practices (BPC section 5.18.1), are to verify that: 
• the rights, safety and protection of the research subjects are met 
• the data reported is exact, complete and consistent with the source documents 
• the research is carried out in accordance with the protocol in force, with the French 
GCPs and with the legislative and regulatory provisions in force 
 

 
 
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13.1.1 Strategy for opening the centres 
The strategy for opening the centres established for this research is determined using the 
appropriate monitoring plan. All centres will be opened simultaneously. 
 
13.1.2 Level of centre monitoring 
 
In the case of this research, which is considered an intermediate risk, the appropriate 
monitoring level has been determined based on the complexity, the impact and the budget for 
the research.  Thus, the sponsor and the coordinating investigator have agreed on the logistic 
score and impact, resulting in a research monitoring level to be implemented: level C. 
Mandatory elements concerning patients’ consent will be fully monitored. As the main endpoint 
is of primarily importance, its level of monitoring will be 100%. Considering a C level of risk, 
which is considered intermediate, the level of monitoring for the safety data will be 100%. Other 
data concerning secondary outcomes will be telemonitored and 25% will be monitored fully.  
 
13.2 Quality control 
A Clinical Research Associate (CRA) appointed by the sponsor will be responsible for the 
proper conduct of the research, for collecting and documenting, recording and reporting the 
data generated in writing, in accordance with the Standard Operating Procedures applied 
within the DRCI and in accordance with the French Good Clinical Practices as well as with the 
legislative and regulatory provisions in force. 
 
The investigator and the members of the investigator's team agree to make themselves 
available during Quality Control visits carried out at regular intervals by the Clinical Research 
Associate. During these visits, the following elements will be reviewed: 
- 
written consent 
- 
compliance with the research protocol and with the procedures defined therein 
- 
quality of the data collected in the case report form: accuracy, missing data, 
consistency of the data with the "source" documents (medical files, appointment books, 
original copies of laboratory results, etc.) 
- 
management of the treatments used 
13.3 Case Report Form 
All information required according to the protocol must be entered in the case report forms. 
The data must be collected as and when they are obtained, and clearly recorded in these case 
report forms. Each missing data item must be coded.  
This digital case report form will be implemented in each centre thanks to a web-based data 
collection medium. Investigators will be given a document offering guidance in using this tool. 
When the investigators complete the case report via the Internet, the CRA can view the data 
quickly and remotely. The investigator is responsible for the accuracy, quality and relevance 
of all the data entered. In addition, the data are immediately verified as they are entered, thanks 
to consistency checks.  Thus, the investigator must validate any changes to the values in the 
case report form. These modifications will be subject to an audit trail. A justification can be 
added when applicable, as a comment. A print-out, authenticated (signed and dated) by the 
investigator, will be requested at the end of the research. The investigator must archive a copy 
of the authenticated document that was delivered to the sponsor. 
 
13.4 Management of non-compliances  
 

 
 
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Any events that occur as a result of non-compliance, by the investigator or any other individual 
involved in conducting the research, with the protocol, with the standard operating procedures, 
with the good clinical practices or with the legislative and regulatory provisions in force must 
be noted in a declaration of non-compliance addressed to the sponsor. As a first step, major 
or critical non-compliances will be reviewed and processed by the DRCI's medical coordinator 
in order to implement the necessary corrective or preventive actions. Next, the non-
compliances will be sent to the Quality - Risk Management Division of the DRCI for verification 
and analysis. These verifications could result in the investigator in charge of the research 
location in question being asked for information or could lead to compliance or audit visits.  
 
13.5 Audits/inspections 
 
The investigators agree to accept the quality assurance audits carried out by the sponsor as 
well as the inspections carried out by the competent authorities. All data, documents and 
reports may be subject to regulatory audits and inspections. Medical secrecy cannot be 
invoked in opposition to these audits and inspections. 
An audit can be carried out at any time by individuals appointed by the sponsor and who are 
not associated with the research directors. The objective of the audit is to ensure the quality of 
the research, the validity of the results and compliance with the legislation and regulations in 
force. 
 
The individuals who lead and monitor the research agree to comply with the sponsor's 
requirements and with the competent authority regarding research audits or inspections. 
 
The audit may be applicable to all stages of the research, from the development of the protocol 
to the publication of the results and the organisation of the data used or produced as part of 
the research. 
 
13.6 Primary investigator's commitment to assume responsibility 
Before starting the research, each investigator will give the sponsor’s representative a copy of 
his/her personal curriculum vitæ, signed and dated, with his/her number in the RPPS 
(Répertoire Partagé des Professionnels de Santé, Collective Database of Health 
Professionals). 
 
Each investigator will undertake to comply with the legislation and to carry out the research 
according to French GCP, adhering to the Declaration of Helsinki terms in force.  
 
The primary investigator at each participating centre will sign a responsibility commitment 
(standard DRCI document) which will be sent to the sponsor's representative. 
The investigators and their employees will sign a delegation of duties form specifying each 
person's role. 
 
13.7 Pharmacist's commitment to assume responsibility  
Each pharmacist will be responsible for the reception, the good storage and management of 
the experimental treatment according to the pharmacy manual (standard DRCI document). 
The employees of the parhamcy involve in the study, will sign a delegation of duties form 
specifying each person’s role. 
 
14 ETHICAL AND LEGAL CONSIDERATIONS  

 
 
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This research will also be conducted in accordance with European laws and 
regulations, the principles of the World Medical Association (WMA) Declaration of 
Helsinki, established by the 18th WMA Assembly (Helsinki, 1964) and subsequent 
amendments, and current ICH GCP guidelines. It will be registered in European 
Medicines Agency (EMA) databases and other sites as appropriate, including the 
US Food & Drug Administration (FDA - clinicaltrials.gov) clinical trials database 
14.1 Methods for obtaining information and consent from research participants  
In accordance with Article L1122-1-1 of the French Public Health Code, no biomedical research 
can be carried out on a person without free and informed consent, obtained in writing after the 
person has been given the information specified in Article L.1122-1 of said Code. 
 
The informed consent will be obtained in the inclusion visit carried out by a physician who is 
part of the research team, in each participating centre. Consent could be obtained from the 
patient, or from a relative if the patient is unable to consent, or using the emergency clause 
according to French Law if no relative could be present within 24 hours. This third party must 
have no association with the investigator or with the sponsor If the patient was unable to 
consent, a pursuit consent will be sought as soon as the patient will be able to express its wills. 
 
The subject will be granted a reflection period of 2 hours between the time when the subject 
receives the information and the time when he or she signs the consent form. 
 
 
The information sheet and a copy of the consent form, signed and dated by the research 
subject and by the investigator or the doctor representing the investigator, are given to the 
individual prior to his or her participation in the research.  
 
In addition, the investigator will specify in the research participant's medical file the methods 
used for obtaining his or her consent or from his relative according to article L. 1122-1-1 à L. 
1122-2 du CSP as well as the methods used for providing information with the goal of obtaining 
their consent. The investigator will retain the original signed and dated copy of the subject's 
consent form. 
 
14.2 Subject prohibited from participating in another research or an exclusion period 
anticipated after the research, if applicable 
The exclusion period specified for this is 6 months as the main outcome is collected at 6 months 
 
During this period, the subject may not participate in other biomedical research protocols 
relating to medications until after 6 months, patients can nevertheless participate to 
observational protocol. 
14.3 Legal obligations  
14.3.1 The sponsor's role 
 
GHU Paris Psychiatrie et Neurosciences is the sponsor of this research and by delegation, the 
Clinical Research and Innovation Office (DRCI) carries out the research's missions in 
accordance with Article L.1121-1 of the French Public Health Code. GHU Paris Psychiatrie et 
Neurosciences reserves the right to halt the research at any time for medical or administrative 
reasons. In this case, notification will be sent to the investigator 
 

 
 
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14.4 Request for an opinion from the Comité de Protection des Personnes (CPP, ethical 
review board) 
Le GHU Paris Psychiatrie et Neurosciences, as sponsor, obtains for this biomedical research 
relating to a medication for human use and prior to starting the research, the favourable opinion 
of the appropriate CPP, within the scope of its authority and in accordance with the legislative 
and regulatory provisions in force. 
 
14.5 Request for authorisation to ANSM 
Le GHU Paris Psychiatrie et Neurosciences, as sponsor, obtains for this biomedical research 
relating to a medication for human use and prior to starting the research, authorisation from 
the ANSM, within the scope of its authority and in accordance with the legislative and 
regulatory provisions in force. 
 
14.6 Commitment to compliance with the MR 001 "Méthodologie de Reference"  
14.7 Le GHU Paris Psychiatrie et Neurosciences, the research sponsor, has signed a 
commitment to comply with this "Méthodologie de reference". 
 
14.8 Standard declaration to the CNIL 
 
This is a multicentric research taking place in 9 hospitals, Le GHU Paris Psychiatrie et 
Neurosciences as sponsor of the research will make a standard declaration to the CNIL.  
 
14.9 Modifications to the research 
Any substantial modification to the protocol by the coordinating investigator must be sent to 
the sponsor for approval. After approval is given, the sponsor must obtain, prior to starting the 
research, a favourable opinion from the CPP and authorisation from the ANSM within the 
scope of their respective authorities.  
The information sheet and the consent form can be revised if necessary, in particular if there 
is a substantial modification to the research or if adverse reactions occur. 
14.10 Final research report 
The final biomedical research report referred to in Article R1123-60 of the French Public Health 
Code is drawn up and signed by the sponsor and the investigator. A summary of the report 
written according to the competent authority’s reference plan will need to be sent to the 
competent authority and ethical review board within one year after the end of the research, 
meaning the end of the participation of the last research subject.  
15 FUNDING AND INSURANCE 
15.1 Funding source  
PHRC is the only funding office seeken for this trial. No complementary industrial funding is 
available at that time. 
 
 
 
15.2 Insurance 
 

 
 
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For the duration of the research, the Sponsor will take out an insurance policy covering the 
sponsor's own civil liability as well as the civil liability of all the doctors involved in carrying out 
the research. The sponsor will also provide full compensation for all harmful consequences of 
the research for the research subjects and their beneficiaries, unless the sponsor can prove 
that the harm is not the fault of the sponsor or any agent. The act of a third party or the voluntary 
withdrawal of the person who initially consented to participate in the research cannot be 
invoked against said compensation. 
 
Le GHU Paris Psychiatrie et Neurosciences has taken out insurance from Relyens Mutual 
Insurance (contract n°163543) located to 18 rue Edouard Rochet 69372 Lyon cedex 08for the 
full research period, covering its own civil liability and that of any agent (doctor or research 
staff), in accordance with Article L.1121-10 of the French Public Health Code. 
 
 
16 PUBLICATION RULES 
- A study group will be constituted for the publication. The main investigator will be listed 
as first author, the methodologist as second author, the scientific advisor last author, the 
investigators will be listed individually in order of inclusions number 
 
 
16.1 Mention of the affiliation of Le GHU Paris Psychiatrie et Neurosciences for projects 
sponsored or managed by Le GHU Paris Psychiatrie et Neurosciences 
 
- "The sponsor was Le GHU Paris Psychiatrie et Neurosciences (Délégation à la 
Recherche Clinique et à l’Innovation)" 
 
 
16.2 Mention of the Le GHU Paris Psychiatrie et Neurosciences manager (DRCI) in the 
acknowledgements of the text 
- "The sponsor was Le GHU Paris Psychiatrie et Neurosciences (Délégation à la 
Recherche Clinique et à l’Innovation)"  
 
16.3 Mention of the financier in the acknowledgements of the text 
- The research was funded by a grant from Programme Hospitalier de Recherche Clinique 
- PHRC 2023 (Ministère de la Santé) 
 
17 BIBLIOGRAPHY 
 
1 
Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. 
Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a 
prospective hospital based cohort study in the Netherlands. J Neurol Neurosurg Psychiatry 
2000; 68: 337–41. 
2 
Geraghty JR, Testai FD. Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: 
Beyond Vasospasm and Towards a Multifactorial Pathophysiology. Curr Atheroscler Rep 
2017; 19: 50. 

 
 
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3 
Macdonald RL, Higashida RT, Keller E, et al. Clazosentan, an endothelin receptor 
antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical 
clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). 
Lancet Neurol 2011; 10: 618–25. 
4 
Fujinaga K, Onoda K, Yamamoto K, et al. Locally applied cilostazol suppresses 
neointimal hyperplasia by inhibiting tenascin-C synthesis and smooth muscle cell proliferation 
in free artery grafts. J Thorac Cardiovasc Surg 2004; 128: 357–63. 
5 
Nakatsuka Y, Kawakita F, Yasuda R, et al. Preventive effects of cilostazol against the 
development of shunt-dependent hydrocephalus after subarachnoid hemorrhage. J Neurosurg 
2017; 127: 319–26. 
6 
Yamaguchi-Okada M, Nishizawa S, Mizutani A, Namba H. Multifaceted effects of 
selective inhibitor of phosphodiesterase III, cilostazol, for cerebral vasospasm after 
subarachnoid hemorrhage in a dog model. Cerebrovasc Dis 2009; 28: 135–42. 
7 
Hackett ML, Anderson CS. Health outcomes 1 year after subarachnoid hemorrhage: 
An international population-based study. The Australian Cooperative Research on 
Subarachnoid Hemorrhage Study Group. Neurology 2000; 55: 658–62. 
8 
Dorsch N. A clinical review of cerebral vasospasm and delayed ischaemia following 
aneurysm rupture. Acta Neurochir Suppl 2011; 110: 5–6. 
9 
Ferguson S, Macdonald RL. Predictors of cerebral infarction in patients with 
aneurysmal subarachnoid hemorrhage. Neurosurgery 2007; 60: 658–67; discussion 667. 
10 
Petruk KC, West M, Mohr G, et al. Nimodipine treatment in poor-grade aneurysm 
patients. Results of a multicenter double-blind placebo-controlled trial. J Neurosurg 1988; 68: 
505–17. 
11 
Boulouis G, Labeyrie MA, Raymond J, et al. Treatment of cerebral vasospasm following 
aneurysmal subarachnoid haemorrhage: a systematic review and meta-analysis. Eur Radiol 
2017; 27: 3333–42. 
12 
Suzuki S, Sayama T, Nakamura T, et al. Cilostazol improves outcome after 
subarachnoid hemorrhage: a preliminary report. Cerebrovasc Dis 2011; 32: 89–93. 
13 
Senbokuya N, Kinouchi H, Kanemaru K, et al. Effects of cilostazol on cerebral 
vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, 
randomized, open-label blinded end point trial. 2013; published online Jan 1. 
DOI:10.3171/2012.9.JNS12492. 
14 
Matsuda N, Naraoka M, Ohkuma H, et al. Effect of Cilostazol on Cerebral Vasospasm 
and Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Randomized, 
Double-Blind, Placebo-Controlled Trial. Cerebrovasc Dis 2016; 42: 97–105. 
15 
Sugimoto K, Nomura S, Shirao S, et al. Cilostazol decreases duration of spreading 
depolarization and spreading ischemia after aneurysmal subarachnoid hemorrhage. Ann 
Neurol 2018; 84: 873–85. 
16 
Bohara S, Garg K, Singh Rajpal PM, Kasliwal M. Role of Cilostazol in Prevention of 
Vasospasm After Aneurysmal Subarachnoid Hemorrhage-A Systematic Review, Meta-
Analysis, and Trial Sequential Analysis. World Neurosurg 2021; 150: 161–70. 
17 
Kim K, Kim B-H, Lim KS, et al. Potential interactions between cilostazol and probucol: 
A two-part, single-dose, open-label study in healthy Korean male volunteers. Clinical 
Therapeutics 2009; 31: 2098–106. 
18 
Choi, H. L, Sang HL, et al. Pharmacokinetics and correlation analysis of cilostazol in 
healthy Korean subjects. International journal of clinical pharmacology and therapeutics 2012. 
DOI:10.5414/CP201671. 
19 
Jung-Ryul K, J. J, Seokuee K, et al. Effect of Cilostazol on the Pharmacokinetics of 
Simvastatin 
in 
Healthy 
Subjects. 
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DOI:10.1155/2019/1365180. 
20 
Suri A, W. F, S. B. Pharmacokinetics of MultipleDose Oral Cilostazol in MiddleAge and 
Elderly Men and Women. Journal of clinical pharmacology 1998. DOI:10.1002/j.1552-
4604.1998.tb04403.x. 

 
 
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21 
Heedoo Y, HeaYoung C, Yong-Bok L. Population pharmacokinetic analysis of 
cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1. 
British Journal of Clinical Pharmacology 2010. DOI:10.1111/j.1365-2125.2009.03558.x. 
22 
Heedoo Y, S.-A. P, H-Y C, Y.B. L. Influence of CYP3A and CYP2C19 Genetic 
Polymorphisms on the Pharmacokinetics of Cilostazol in Healthy Subjects. Clinical 
pharmacology and therapy 2009. DOI:10.1038/clpt.2009.90. 
23 
Niki T, H. M. Phase I study of cilostazol. Safety evaluation at increasing single doses 
in healthy volunteers. Arzneimittel-Forschung 1985. 
24 
Lee D, Son H, Lim LA, Park K. Population Pharmacokinetic Analysis of Diurnal and 
Seasonal Variations of Plasma Concentrations of Cilostazol in Healthy Volunteers. 
Therapeutic Drug Monitoring 2014; 36: 771–80. 
25 
Yokoyama T, Yamauchi S, Yamagata K, et al. Impact of Cilostazol Pharmacokinetics 
on the Development of Cardiovascular Side Effects in Patients with Cerebral Infarction. 
Biological and Pharmaceutical Bulletin 2021; 44: 1767–74. 
26 
Woo S, W. K, K. K. Pharmacokinetic and pharmacodynamic modeling of the antiplatelet 
and cardiovascular effects of cilostazol in healthy humans. Clinical pharmacology and therapy 
2002. DOI:10.1067/mcp.2002.122474. 
27 
Wilson JTL, Hareendran A, Hendry A, Potter J, Bone I, Muir KW. Reliability of the 
Modified Rankin Scale Across Multiple Raters. Stroke 2005; 36: 777–81. 
28 
Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: 
implications for stroke clinical trials: a literature review and synthesis. Stroke 2007; 38: 1091–
6. 
29 
Modak AS, Klyarytska I, Kriviy V, Tsapyak T, Rabotyagova Y. The effect of proton pump 
inhibitors on the CYP2C19 enzyme activity evaluated by the pantoprazole-13C breath test in 
GERD patients: clinical relevance for personalized medicine. J Breath Res 2016; 10: 046017. 
 
 
 
18 LIST OF ADDENDA 
18.1 List of Investigators  
National multicenter research  
 
18.2 Form for reporting Serious Adverse Events 
eCRF 
 
18.3 Questionnaire or scale 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix 1 Modified Rankin with Structured Interview 

 
 
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Appendix 2 Subarachnoid hemorrhage outcome tool  
 
 
 

 
 
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Appendix 3 MOCA Score 
 
 
 

 
 
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Appendix 4 Activities of a daily living 
 
 
 

 
 
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Appendix 5 Instrumental activities of a daily living 
 
 
 
 
 
 
 
 

 
 
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Appendix 6 Charlson Score 
 
 
Appendix 7 Therapy intensity level 
 
TIL 0: No specific ICP directed therapy  
TIL 1 – basic ICU care : 
- Sedation for ventilator/endotracheal tube tolerance  
- Volume/vasopressors for non-CNS cause (e.g. sepsis, myocardial injury)  
- Head up positioning (ventilator bundle)  
- Normocapnia (PaCO2 ≥ 40mmHg)  
 
TIL 2 – Mild : 
- Higher levels of sedation  
- Vasopressors/volume for CPP support  
- Low dose osmotic therapy  
- Mild hypocapnia (PaCO2 4.6-5.3 kPa; 35-40 mmHg)  
- CSF drainage < 120 ml/day (<5 ml/hour)  
 
TIL 3 – Moderate  
- Higher doses of osmotic therapy  
- Moderate hypocapnia (PaCO2 4.0-4.5 kPa; 30-35 mmHg)  
- Mild hypothermia (> 35 °C)  
- CSF drainage ≥ 120 ml/day (>5 ml/hour)  
 
TIL 4 – Extreme  
- Profound hypocapnia (PaCO2 < 4.0 kPa; < 30 mmHg)  
- Hypothermia < 35 °C  
- Metabolic suppression for control of ICP  
- Surgery for refractory ICP (decompression, lobectomy) 
 
 

 
 
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Appendix 8 Network meta-analysis for indirect treatment comparisons 
 
Reference is made to a network meta-analysis [Dayyany, 2022] that tests the efficacy of 
prophylactic therapies for aSAH. 
The literature search of the referenced network meta-analysis stopped in February 2020; 
therefore, an update was performed on Medline according to the same strategies from February 
2020 to December 2022. 
The search strategies are reported below. 
 
Appendix 9 Fisher Scale 
 
Search strategies 
 
PUBMED 
Search query:  
(("clinical trial"[All Fields] OR "clinical trials as topic"[All Fields] OR "clinical trial"[All 
Fields]) AND ("intracranial aneurysm"[All Fields] OR ("intracranial aneurysm"[MeSH Terms] 
OR ("intracranial"[All Fields] AND "aneurysm"[All Fields]) OR "intracranial aneurysm"[All 
Fields])) AND ("subarachnoid hemorrhage"[All Fields] OR ("aneurysmal subarachnoid 
haemorrhage"[All 
Fields] 
OR 
"subarachnoid 
hemorrhage"[MeSH 
Terms] 
OR 
("subarachnoid"[All 
Fields] 
AND 
"hemorrhage"[All 
Fields]) 
OR 
"subarachnoid 
hemorrhage"[All Fields] OR ("aneurysmal"[All Fields] AND "subarachnoid"[All Fields] AND 
"hemorrhage"[All Fields]) OR "aneurysmal subarachnoid hemorrhage"[All Fields])) AND 
("vasospasm intracranial"[All Fields] OR ("vasospasm, intracranial"[MeSH Terms] OR 
("vasospasm"[All Fields] AND "intracranial"[All Fields]) OR "intracranial vasospasm"[All 
Fields] OR ("cerebral"[All Fields] AND "vasospasm"[All Fields]) OR "cerebral 
vasospasm"[All Fields])) AND (("clinical trial"[All Fields] OR "clinical trials as topic"[All 
Fields] OR "clinical trial"[All Fields]) AND ("intracranial aneurysm"[All Fields] OR 

 
 
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("intracranial aneurysm"[MeSH Terms] OR ("intracranial"[All Fields] AND "aneurysm"[All 
Fields]) OR "intracranial aneurysm"[All Fields])) AND ("subarachnoid hemorrhage"[All 
Fields] OR ("aneurysmal subarachnoid haemorrhage"[All Fields] OR "subarachnoid 
hemorrhage"[MeSH Terms] OR ("subarachnoid"[All Fields] AND "hemorrhage"[All Fields]) 
OR 
"subarachnoid 
hemorrhage"[All 
Fields] 
OR 
("aneurysmal"[All 
Fields] 
AND 
"subarachnoid"[All Fields] AND "hemorrhage"[All Fields]) OR "aneurysmal subarachnoid 
hemorrhage"[All Fields])) AND ("vasospasm intracranial"[All Fields] OR ("vasospasm, 
intracranial"[MeSH Terms] OR ("vasospasm"[All Fields] AND "intracranial"[All Fields]) OR 
"intracranial vasospasm"[All Fields] OR ("cerebral"[All Fields] AND "vasospasm"[All Fields]) 
OR "cerebral vasospasm"[All Fields])))) AND (2020/2/1:2022/12/31[pdat])  
 
Results 10 
Ten new references were identified, none of which were suitable for the objective of the net-
work meta-analysis. 
Therefore, for the network meta-analysis, trials using nimodipine, cilostazol or fasudil (the 
usual comparator for cilostazol) as prophylaxis in at least one arm of the study were selected. 
Concerning the outcome as per the main objective of the CASH study (mRS assessed at six 
months, where the favourable outcome is defined as the mRS score of 0 to 2, and unfavourable 
outcome of 3 to 6) for the studies where the assessment was made using the GOSE scale, the 
results were converted as in Table S1. The meta-analysis was performed with MetaXL Version 
5.3 (EpiGear International Pty Ltd -ABN 51 134 897 411 Sunrise Beach, Queensland, Australia, 2011-2016), a 
fixed-effects model was used, and the method for calculating the weighted average effect was 
the inverse of variance heterogeneity. The global heterogeneity of the model was assessed using 
the H inconsistency index H is the estimated residual variance of the standardized treatment effect estimates 
against the inverse standard error in each synthesis (Higgins and Thompson 2002); The interpretation is that H <3 
indicates minimal inconsistency of treatment effects (the minimum possible H is 1). Values between 3 and 6 
indicate modest network inconsistency and values > 6 suggest gross network inconsistency 
Table S1: GOSE vs mRS conversion table 
Modified Rankin Scale (mRS) 
Glasgow Outcome Scale (GOS) 
0 - No symptoms. 
4 -  Moderate disability 
5 -  Low disability 
1 - No significant disability. Able to carry out all usual 
activities, despite some symptoms. 
2 - Slight disability. Able to look after own affairs 
without assistance, but unable to carry out all previous 
activities. 
3 - Moderate disability. Requires some help, but able to 
walk unassisted. 
1 -  Death 
2 -  Persistent vegetative state 
3 -  Severe disability 
4 - Moderately severe disability. Unable to attend to own 
bodily needs without assistance, and unable to walk 
unassisted. 
5 - Severe disability. Requires constant nursing care and 
attention, bedridden, incontinent. 
6 - Dead. 
  

 
 
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Tables S2a, S2b, S2c and S2d shows the characteristics of the trials included in the network 
meta-analysis and the risk of bias assessment. 
Table S2a: Characteristics of the trials included in the network meta-analysis 
  
Ref 
Study (year) 
Location 
Setting 
Age 
(yr) 
Gender 
(female %) 
1 
Petruk (1988) 
17 centers in Canada 
Multicenter 
54.9 
66.6 
2 
Pickard (1989) 
UK 
Multicenter 
47.0 
60.1 
3 
Ohman (1991) 
Finland 
Single-center 
45.1 
51.4 
4 
Shibuya (1992) 
60 centers in Japan 
Multicenter 
55.0 
56.0 
5  
Zhao (2006) 
5 centers in China 
Multicenter 
50.1 
61.1 
6 
Zhao (2011) 
5 centers in China 
Multicenter 
50.0 
61.2 
7 
Suzuki (2011) 
5 centers in Japan 
Multicenter 
63.0 
76.0 
8 
Sembokuya (2013) 
7 centers in Japan 
Multicenter 
60.6 
62.4 
9 
Matsuda (2016) 
5 centers in Japan 
Multicenter 
58.5 
67.5 
 
 
  
Table S2b: Treatment characteristics of trials and outcomes included in the network 
meta-analysis 
  
R
e
f 
Study 
(year) 
Experi
mental 
arm 
Pt
s. 
N
b 
Dose 
Dura
tion 
(days
) 
Contro
l arm 
Pt
s. 
N
b 
Dos
e 
Durat
ion 
(days) 
Outco
mes 
Concomi
tant 
treatmen
t 
Length 
follow-
up 
1 
Petruk 
(1988) 
Nimodi
pine 
91 
90mg/q
4h 
21 
placeb
o 
97 
- 
- 
Mortali
ty, 
Vasosp
asm, 
DCI, 
GOS 
Hypervol
emia and 
hypertens
ion 
3 
months 
2 
Pickard 
(1989) 
Nimodi
pine 
27
8 
30mg/q
4h 
21 
placeb
o 
27
6 
- 
- 
Mortali
ty, 
DCI,G
OS 
- 
3 
months 
3 
Ohman 
(1991) 
Nimodi
pine 
10
4 
Iv 
5mcg/k
g/min 
then 60 
po 
21 
placeb
o 
10
9 
- 
- 
Mortali
ty, 
DCI, 
GOS 
- 
3 years 
4 
Shibuya 
(1992) 
Fasudil 
13
6 
30mg iv 
136 
placeb
o 
14
0 
- 
- 
Mortali
ty, 
Vasosp
asm, 
DCI, 
GOS 
- 
1 
months 
5 
Zhao 
(2006) 
Fasudil 
37 
30 mg 
iv 
14 
Nimod
ipine 
35 
1 
mg/
h iv 
14 
Mortali
ty, 
Vasosp
asm, 
DCI, 
GOS 
- 
1 
months 

 
 
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6 
Zhao 
(2011) 
Fasudil 
63 
30 mg 
iv 
14 
Nimod
ipine 
66 
0.5-
1 
mg/
h 
then 
1-2 
mg/
h iv 
14 
Mortali
ty, 
DCI, 
GOS 
- 
1 
months 
7 
Suzuki 
(2011) 
Cilostaz
ol 
49 
200mg/
d 
14 
Contro
l 
51 
- 
- 
Mortali
ty, 
DCI, 
mRS 
Triple H 
therapy, 
fasudil 
hydrochl
oride 
and/oroza
grel Na 
14 days 
8 
Sembokuya 
(2013) 
Cilostaz
ol 
54 
200mg/
d 
14 
Contro
l 
55 
  
  
Mortali
ty, 
Vasosp
asm, 
DCI, 
GOS 
Fasudil 
hydrochl
oride 
6 
months 
9 
Matsuda 
(2016) 
Cilostaz
ol 
74 
200mg/
d 
14 
Placeb
o 
74 
  
  
Mortali
ty, 
Vasosp
asm, 
DCI, 
GOS 
Fasudil 
hydrochl
oride 
3 
months 
  
  
  
Table S2c: Summary of risk of bias assessment for included trials in the network meta-
analysis 
Ref 
Study 
(year) 
Sequen
ce 
generat
ion 
Study 
(year) 
Allocati
on 
Concea
lment 
Blindin
g of 
Partici
pants 
Blindin
g of 
health 
care 
provide
rs 
  
Blindin
g of 
Outco
me 
Assess
ment 
  
Missing 
particip
ant 
data 
Select
ive 
repor
ting 
  
Source of 
Funding 
1 
Petruk 
(1988) 
Low 
Low 
Low 
Low 
Low 
Low 
Low 
No funding 
statement 
2 
Pickard 
(1989) 
Low 
Low 
Low 
Low 
Low 
Low 
Low 
Industry 
3 
Ohman 
(1991) 
Low 
High 
Low 
Low 
Low 
Low 
Low 
No funding 
statement 
4 
Shibuya 
(1992) 
Low 
High 
Low 
Low 
Low 
Low 
Low 
No funding 
statement 
5 
Zhao 
(2006) 
Low 
High 
High 
High 
High 
Low 
Low 
No funding 
statement 
6 
Zhao 
(2011) 
Low 
High 
High 
High 
High 
High 
Low 
No funding 
statement 
7 
Suzuki 
(2011) 
Low 
High 
High 
High 
Low 
Low 
Low 
No funding 
statement 
8 
Sembokuya 
(2013) 
Low 
Low 
High 
High 
Low 
Low 
Low 
No funding 
statement 
9 
Matsuda 
(2016) 
Low 
Low 
Low 
High 
Low 
Low 
Low 
No funding 
statement 
  

 
 
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Page 72 / 76 
 
  
 Table S2d: Trials selected for network meta-analysis and events for each study arm 
favourable outcome at the longest follow-up 
 
 
 
Active 
Control 
Active 
Control 
Study name 
Nb 
Case
s 
Non-
cases 
Nb 
Case
s 
Non-
cases 
Nimodipina 
Placebo 
Petruk,1988 
72 
28 
44 
82 
28 
54 
Nimodipina 
Placebo 
Pickard, 1989 
278 
223 
55 
276 
185 
91 
Nimodipina 
Placebo 
Ohman, 1991 
104 
86 
18 
109 
86 
23 
Fasudil 
Placebo 
Shibuya, 1992 
136 
98 
38 
136 
95 
41 
Fasudil  
Nimodipin
a 
Zhao, 2006 
33 
27 
6 
34 
28 
6 
Fasudil plus 
Nimodipine 
Nimodipin
a 
Zhao_2, 2011 
55 
49 
6 
60 
48 
12 
Cilostazol plus Fasudil 
Fasudil 
Suzuki, 2011 
49 
39 
10 
51 
24 
27 
Cilostazol plus Fasudil 
Fasudil 
Sembukuya, 
2013 
54 
39 
15 
55 
36 
19 
Cilostazol 
Placebo 
Matsuda, 2016 
74 
60 
14 
74 
61 
13 
 
 
 
855 
649 
206 
877 
591 
286 
  
The results of the network meta-analysis versus nimodipine are shown in Table S3 and Figures 
S1 and S2. 
The model shows excellent consistency (H=1.0). The interpretation is that H <3 indicates minimal 
inconsistency of treatment effects (the minimum possible H is 1). Values between 3 and 6 indicate modest network 
inconsistency and values > 6 suggest gross network inconsistency. 
 
 
Table S3: Network meta-analysis vs nimodipine 
ID 
Comparison 
Active 
Contr
ol 
OR 
LCI 
95% 
UCI 
95% 
 
Direct estimates 
 
 
 
 
 
1 
Nimodipine vs Placebo 
Nimodipine 
Placeb
o 
1.655 
1.226 
2.235 
2 
Fasudil vs placebo 
Fasudil 
Placeb
o 
1.113 
0.659 
1.879 
3 
Fasudil vs Nimodipine 
Fasudil 
Nimod
ipine 
0.964 
0.277 
3.362 
4 
Fasudil plus Nimodipine vs Nimodipine 
Fasudil plus 
Nimodipine 
Nimod
ipine 
2.042 
0.709 
5.880 
5 
Cilostazol plus Fasudil vs Fasudil 
Cilostazol plus 
Fasudil 
Fasudi
l 
2.337 
1.283 
4.257 
6 
Cilostazol vs Placebo 
Cilostazol 
Placeb
o 
0.913 
0.396 
2.105 
 
 
 
 
 
 
 
 
Indirect estimates (source IDs) 
 
 
 
 
 
7 
Indirect Cilostazol plus Fasudil vs Nimodipine 
(5, 3) 
Cilostazol plus 
Fasudil 
Nimod
ipine 
2.253 
0.564 
9.007 

 
 
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8 
Indirect Placebo vs Nimodipine (2, 3) 
Placebo 
Nimod
ipine 
0.866 
0.224 
3.357 
9 
Indirect Fasudil vs Nimodipine (2, 1) 
Fasudil 
Nimod
ipine 
0.672 
0.368 
1.230 
10 
Indirect Cilostazol vs Nimodipine (6, 1) 
Cilostazol 
Nimod
ipine 
0.552 
0.227 
1.340 
 
 
 
 
 
 
 
 
Result estimates (source IDs) 
 
 
 
 
 
 
Placebo (1, 8) 
Placebo 
Nimod
ipine 
0.614 
0.458 
0.824 
 
Fasudil (3, 9) 
Fasudil 
Nimod
ipine 
0.720 
0.418 
1.240 
 
Fasudil plus Nimodipine (4) 
Fasudil plus 
Nimodipine 
Nimod
ipine 
2.042 
0.709 
5.880 
 
Cilostazol plus Fasudil (7) 
Cilostazol plus 
Fasudil 
Nimod
ipine 
2.253 
0.564 
9.007 
 
Cilostazol (10) 
Cilostazol 
Nimod
ipine 
0.552 
0.227 
1.340 
 
 
Figure S1. Forest plot 
 
 
Figure S2. Network plot 
  

 
 
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Page 74 / 76 
 
 The network meta-analysis versus nimodipine, where the outcome is the patient's status at six 
months, shows a non-inferiority of fasudil versus nimodipine (OR=0.720; 95% CI unilateral 
lower bound =0.050). 
The efficacy trend of the combination of fasudil plus cilostazol  (OR= 2.25; 95% CI unilateral 
lower bound=0.705) and fasudil plus nimodipine (OR=2.04; 95% CI unilateral lower 
bound=0.840) compared to treatment with nimodipine alone appears to be sharper. 
Considering that in both Japan and China, the standard prophylaxis after SAH is fasudil plus 
cilostazol, considering only trials evaluating combination versus monotherapy with nimodipine 
or fasudil, the greater efficacy of combination therapy is apparent. 
The results of the meta-analysis and the forest plot are reported below. A low heterogeneity 
was found (I2=0.45; p=0.16); therefore, the inverse variance heterogeneity model was applied 
(Doi, 2015) 
 
 
Study 
OR 
LCI 95% 
UCI 95% 
Weight 
(%) 
Zhao_2, 2011 (fasudil plus nimodipine vs 
nimodipine) 
2.042 
0.709 
5.880 
24.322 
Suzuki, 2011 (fasudil plus cilostazol vs fasudil) 
4.388 
1.809 
10.641 
34.665 
Sembukuya, 2013 (fasudil plus cilostazol vs 
fasudil) 
1.372 
0.608 
3.099 
41.013 
Pooled 
2.261 
1.108 
4.614 
100.000 
Statistics  
 
 
 
I-squared 
44.9 
 
 
 
Cochran's Q 
3.63 
 
 
 
Chi2, p 
0.163 
 
 
 
  
  
  

 
 
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Page 75 / 76 
 
 
 
 
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1. Petruk KC, West M, Mohr G, Weir BK, Benoit BG, Gentili F, Disney LB, Khan MI, Grace 
M, Holness RO. Nimodipine treatment in poor-grade aneurysm patients. Results of a 
multicenter double-blind placebo-controlled trial. JNeurosurg. 1988;68:505–517.  doi: 
10.3171/jns.1988.68.4.0505 
  
2. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey 
PR, Lang DA, Nelson R, Richards P. Effect of oral nimodipine on cerebral infarction 
and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 
1989;298:636–642. doi: 10.1136/bmj.298.6674.636 
  
3. Ohman J, Servo A, Heiskanen O. Long-term effects of nimodipine on cerebral infarcts 
and outcome after aneurysmal subarachnoid hemorrhage and surgery. J Neurosurg. 
1991;74:8–13. doi: 10.3171/jns.1991.74.1.0008 
  

 
 
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Takemae T, Hidaka H. Effect of AT877 on cerebral vasospasm after aneurysmal 
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al; Fasudil Aneurysmal Subarachnoid Hemorrhage Study Group. Efficacy and safety of 
fasudil in patients with subarachnoid hemorrhage: final results of a randomized trial of 
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Doi, S. A., J. J. Barendregt, S. Khan, L. Thalib and G. M. Williams (2015). 
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