Middle Meningeal Artery (MMA) Embolization for cSDH: Rationale and Design for the STOp Recurrence of MMA Bleeding (STORMM) Randomized-Control Trial
Phase: NA
Conditions: Chronic Subdural Hematomas, Cerebral Compression Due to Injury
Sponsor: University Hospital, Geneva

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
1 
 
Middle Meningeal Artery (MMA) Embolization for cSDH: Rationale and 
Design for the STOp Recurrence of MMA Bleeding (STORMM) 
Randomized-Control Trial 
 
Swiss ID: 2023-00848 
NCT number: NCT06163547 
Protocol date: September 25, 2024 
 
 
Study Type: 
 Other Clinical Trial according to ClinO, Chapter 4 
 
Risk Categorization:  
Risk category B according to ClinO, Art. 61 
 
Study Registration: 
Intended registries: Swiss National Clinical Trial Portal and WHO 
International Clinical Trials Registry Platform 
 
 
 
Sponsor: 
 
 
Prof. Karl Schaller 
Service de neurochirurgie 
Département des neurosciences cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Téléphone : +41 (0) 22 372 82 02 
email: Karl.Schaller@hcuge.ch  
 
 
 
Principal Investigator: 
Dr. Aria Nouri 
Service de neurochirurgie 
Département des neurosciences cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Tel. +41 (0) 795530958 
Email: aria.nouri@hcuge.ch 
 
 
 
Other Investigators :  
Prof Paolo Machi 
 
 
 
 
Service de Neuroradiologie diagnostique et interventionnelle 
 
 
 
 
Unité de neuroradiologie interventionnelle 
Département des neurosciences cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
 
 
 
 
Email : paolo.machi@hug.ch 
 
 
 
 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
2 
 
Dr. Caterina Mollica 
Service de neurochirurgie 
Département des neurosciences cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Email: caterina.mollica@hcuge.ch 
 
Neurocenter of the Southern Switzerland 
Department of Neurosurgery 
Via Tesserete 46 
6900 Lugano 
Switzerland 
 
Dr. Abdullah Awadhi 
Service de neurochirurgie 
Département des neurosciences cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Tel. +41 (0) 795533770 
Email: abdullah.alawadhi@hcuge.ch 
 
Investigated Intervention: 
Middle Meningeal Artery Embolization for Chronic Subdural 
Hematomas 
 
Protocol ID 
 
 
2023-00848 
 
Version and Date: 
 
Version 2.0 (25.09.2024) 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of Prof. Karl Schaller, 
and Dr. Aria Nouri. The information may not - in full or in part - be transmitted, reproduced, 
published, or disclosed to others than the applicable Competent Ethics Committee(s) and 
Regulatory Authority(ies) without prior written authorisation from the sponsor except to the extent 
necessary to obtain informed consent from those who will participate in the study. 
 
 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
3 
 
PROTOCOL SIGNATURE FORM    
 
 
Study Title 
Middle Meningeal Artery (MMA) Embolization for cSDH: 
STOp 
Recurrence 
of 
MMA 
Bleeding 
(STORMM) 
Randomized-Control Trial 
 
Study ID 
2023-00848 
 
The Sponsor has approved the protocol version 2.0 (dated 25.09.2024) and confirm hereby to 
conduct the study according to the protocol, current version of the World Medical Association 
Declaration of Helsinki, and ICH-GCP guidelines as well as the local legally applicable 
requirements. 
 
 
 
Sponsor: 
 
Name: Pr. Karl Schaller 
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
Principal Investigator: 
 
Name: Dr. Aria Nouri 
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
Local Principal Investigator at study site: 
 
Site: 
Lugano, Switzerland 
Neurocenter of the Southern Switzerland 
Department of Neurosurgery 
Via Tesserete 46 
6900 Lugano 
Switzerland 
 
 
Principal Investigator: Dr. Andrea Cardia 
 
 
 Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
 
 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
4 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS 
4 
GLOSSARY OF ABBREVATIONS 
5 
1 STUDY SYNOPSIS 
6 
2 BACKGROUND AND RATIONALE 
10 
3 STUDY OBJECTIVES AND DESIGN 
10 
2.1 Hypothesis and primary objective 
10 
2.2 Primary and secondary endpoints. 
11 
2.3 Study design 
11 
2.4 Study intervention 
12 
4 STUDY POPULATION AND STUDY PROCEDURES 
12 
3.1 Inclusion and exclusion criteria, justification of study population 
12 
3.2 Recruitment, screening and informed consent procedure 
13 
3.3 Study procedures 
13 
3.4 Withdrawal and discontinuation 
13 
5 STATISTICS AND METHODOLOGY 
14 
4.1. Statistical analysis plan and sample size calculation 
14 
4.2. Handling of missing data and drop-outs 
14 
6 REGULATORY ASPECTS AND SAFETY 
15 
5.1 Local regulations / Declaration of Helsinki 
15 
5.2 (Serious) Adverse Events and notification of safety and protective measures 
15 
5.3 (Periodic) safety reporting 
16 
5.4 Radiation 
16 
5.5 Pregnancy (if applicable) 
16 
5.6 Amendments 
16 
5.7 (Premature) termination of study 
17 
5.8 Insurance 
17 
6 FURTHER ASPECTS 
17 
6.1 Overall ethical considerations 
17 
6.2 Risk-benefit assessment 
17 
7 QUALITY CONTROL AND DATA PROTECTION 
17 
7.1 Quality measures 
17 
7.2 Data recording and source data 
18 
7.3 Confidentiality and coding 
18 
7.4 Retention and destruction of study data 
18 
8  MONITORING AND REGISTRATION 
18 
9. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
19 
10. REFERENCES 
19 
APPENDIX 
20 
 
 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
5 
 
GLOSSARY OF ABBREVATIONS 
 
AE 
Adverse Event 
ASR/DSUR 
Annual Safety Report / Development Safety Report 
BASEC 
Business Administration System for Ethical Committees 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin, in Italian: OSRUm) 
CRF 
Case Report Form 
cSDH 
Chronic Subdural Hematomas  
eCRF 
electronic Case Report Form 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GOS-E 
Glasgow Outcome Scale - Extended 
HRA 
Human Research Act (in German: HFG, in French: LRH, in Italian: LRUm) 
ICH 
International Conference on Harmonisation  
MMA 
Middle Meningeal Artery  
mRS 
modified Rankin Scale 
MGS 
Markwalder Grading Scale 
TDN 
Therapy-Disability-Neurology grading system 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
 
 
 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
6 
 
1 
STUDY SYNOPSIS 
Sponsor 
/ 
Sponsor-
Investigator 
Prof. Karl Schaller 
Service de Neurochirurgie 
Département des Neurosciences Cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Study Title 
Middle Meningeal Artery (MMA) Embolization for cSDH: Rationale and 
Design for the STOp Recurrence of MMA Bleeding Randomized-Control 
Trial 
Short 
Title 
/ 
Study ID 
STORMM 
Protocol 
Version 
and 
Date 
Version 2.0 (25.09.2024) 
Study 
Registration 
Intended registries: Swiss National Clinical Trial Portal and WHO 
International Clinical Trials Registry Platform 
Study 
Category 
and 
Rationale 
 Category B 
Background 
and Rationale  
Chronic Subdural Hematomas (cSHD) are common, and due to cerebral 
compression, often result in neurological impairment and reduced 
consciousness. Surgery is typically performed once neurological symptoms 
develop. Recent studies suggest that arteries nourished by the middle 
meningeal artery (MMA) may be responsible for hematoma progression and 
that MMA embolization is clinically useful. There is less evidence, that 
embolization of MMA also may be a treatment option for individuals without 
surgical treatment. We propose a multicentre study to investigate both 
potentials: (1) Assessment of efficacy of embolization after surgery to 
reduce recurrence and improve outcomes by conducting a randomized trial 
(randomization arms; Arms 1 and 2), (2) Assessment of embolization-
alone efficacy when surgery is contraindicated or refused (embolization-
only arm, Arms 3 and 4). 
Risk / Benefit 
Assessment 
Evidence to support the benefit of MMA embolization remains limited and 
the risk-benefit balance remains unclear. Case series have shown that 
recurrence rates with embolization are much lower, and that embolization is 
generally very safe. Risks associated with neurointerventional procedures 
will be directly discussed with patients or their caretakers as part of the 
conventional consenting procedure. Risks include access site hematoma, 
radiation exposure, vascular injury, brain ischemia, death (theoretic and 
extremely unlikely) and typical risks associated with general or local 
anaesthesia.  The potential efficacy of MMA embolization as a treatment 
therefore requires higher level evidence in the form of randomized control 
trials. 
The benefit of the embolization is a substantial reduction in recurrence of 
cSDH, which has been reported to be as high 1 in 3-4 patients. Recurrence 
of cSDH can lead to additional surgery and complications. 
Objective(s) 
First objective: Evaluate the recurrence rates of cSDH after combined 
surgical and MMA embolization treatments (Arm 2) versus surgery alone 
(Arms 1). 
Second objective: The second objective is to evaluate the stability and 
regression of cSDH after for all the Arms of the study at follow-up. 
Endpoint(s) 
Primary endpoint: Clinical finding of recurrence of cSDH: surgical 
reoperation, neurological deterioration due to a cSDH after evacuation, post-

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
7 
 
operative hematoma volume of more than 90% of the preoperative volume 
at follow-up. 
Additional endpoints: Glasgow Coma Scale (GCS), modified Ranking 
Scale (mRS), Markwalder Grading Scale (MGS), Glasgow Outcome Scale 
– Extended (GOS-E), Karnofsky Performance Score (KPS), Therapy-
Disability-Neurology grading system (TDN), mortality rate, and re-
hospitalisation for all causes. 
Study Design 
This study is a multicentre randomised-controlled trial. 
Statistical 
Considerations 
The incidence rates of cSDH recurrence is estimated at 20% and recurrence 
with MMA at 5%. With an alpha = 0.05 and a power of 80%, we estimate 
that a minimum of 156 patients (https://clincalc.com/stats/samplesize.aspx) 
need to be enrolled. Assuming a 15% loss of follow-up, 180 patients need 
to be enrolled in the study. It is therefore planned to enrol a total of 180 
patients, with the aim of 60 patients per centre, however, this is flexible. 
Inclusion- 
/ 
Exclusion 
Criteria 
Inclusion Criteria: (Appendix 1) 
- Age 18-100 years 
- Consent possible 
- cSDH located at the cerebral convexities 
- Patients with symptomatic cSDH 
- Patients with asymptomatic large chronic/subacute hematoma after 6 
weeks of failed conservative treatment. 
 
Exclusion Criteria:  
- Consent not possible  
- Pregnancy 
- Prisoner 
- Angiography contraindication 
-Patient for whom follow-up is problematic (e.g. distant residency, homeless)  
- Previous surgery for cSDH 
 
Exclusion for Randomization arms (Arms 1 and 2), but inclusion for 
embolization-only arms (Arms 3 and 4): 
- Surgery not performed due to significant surgical contraindications 
- Refusal of surgical treatment 
Number 
of 
Participants 
with Rationale 
We estimate that a minimum of 156 patients need to be enrolled. Assuming 
a 15% loss of follow-up, a total of 180 patients needs to be enrolled in the 
study. 
Study 
Intervention 
Patients who undergo surgical treatment will be randomized into receiving 
embolization within 72 hours post-surgery (Arm 2) or no-embolization post-
surgery (conventional management, Arm 1). Patients will be randomized at 
rate of 2 MMA embolization to 1 conventional management. 
Patients who are excluded for surgery due to significant medical 
contraindications (e.g. severe thrombocytopenia or double anti-thrombotic 
therapy without imminent danger of death) or patients who refuse surgery, 
will be considered for embolization only (Arms 3 and 4). 
Control 
Intervention 
Arm 1:  conventional management 
Study 
procedures 
Patients who undergo surgical treatment will be randomized into receiving 
embolization within 72 hours post-surgery (Arm 2) or no-embolization post-
surgery (conventional management, Arm 1). Patients will be randomized at 
rate of 2 MMA embolization to 1 conventional management. 
 
Patients who are excluded for surgery due to significant medical 
contraindications (e.g. severe thrombocytopenia or double anti-thrombotic 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
8 
 
therapy without imminent danger of death) or patients who refuse surgery, 
will be considered for embolization only (Arms 3 and 4). 
 
The details of study intervention are shown in the schedule assessments 
(Appendix 2). 
 
The recorded data to evaluate the recurrence of cSDH are surgical 
reoperation within 6 months but after 72 hours or after embolization, 
neurological deterioration due to a cSDH after evacuation, post-operative 
hematoma volume of more than 90% of the preoperative volume at follow-
up. Additional outcomes such Glasgow Coma Scale (GCS), modified 
Ranking Scale (mRS), Markwalder Grading Scale (MGS), Glasgow 
Outcome Scale – Extended (GOS-E), Karnofsky Performance Score (KPS) 
and the Therapy-Disability-Neurology grading system (TDN) will be 
recorded (Appendix 3). 
Study Duration 
and Schedule 
The study will be undertaken at multiple trauma centres in Europe with the 
objective to enrol patients within an 18-24-month time-frame.  
With the last follow-up planned at 6 months, the combined study duration is 
expected to be no longer than 24-30 months. 
Planned 10/2024 of First-Participant-In. 
Planned 04/2027 of Last-Participant-Out. 
 
 
Investigator(s) 
Principal Investigator at Geneva site:  
Dr. Aria Nouri 
Division of Neurosurgery 
HUG 
Rue Gabrielle Perret-Gentil 4 
1211 Genève 14 
Switzerland 
Tel. +41 (0) 795530958 
Email:  aria.nouri@hcuge.ch 
 
Principal Investigator at Lugano site:  
Dr. Andrea Cardia 
Neurocenter of the Southern Switzerland 
Department of Neurosurgery 
Via Tesserete 46 
6900 Lugano 
Switzerland 
 
Other Investigators :  
Prof Paolo Machi 
Service de Neuroradiologie diagnostique et interventionnelle 
Unité de neuroradiologie interventionnelle 
Département des neurosciences cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Email : paolo.machi@hug.ch 
 
Dr. Caterina Mollica 
Service de neurochirurgie 
Département des neurosciences cliniques HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Email: caterina.mollica@hcuge.ch 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
9 
 
 
Neurocenter of the Southern Switzerland 
Department of Neurosurgery 
Via Tesserete 46 
6900 Lugano 
Switzerland 
 
Dr. Abdullah Awadhi 
Service de neurochirurgie 
Département des neurosciences cliniques 
HUG 
Rue Gabriel-Perret-Gentil, 4 
1211 Genève 14 
Tel. +41 (0) 795533770 
Email: abdullah.alawadhi@hcuge.ch 
 
Study 
Center(s) 
2 Swiss centres are involved in the study: Geneva and Lugano 
 
Data privacy 
Data privacy will be ensured through anonymization end encoding of all 
patients’ data.  
Ethical 
consideration 
While it has been shown that the MMA embolization can reduce recurrence, 
this has not yet been demonstrated with high-level evidence. As low risks 
exist with the neuro-interventional procedures, there is a need for high level 
of evidence studies by randomizing patients to evaluate the potential 
benefits and to determine if these clearly outweigh the risks and costs of 
MMA embolization. Peer review publications and presentations of the 
results at international meetings are planned. 
The process of embolization requires another general anaesthesia, and 
while angiographic procedures are generally well tolerated, undertaking this 
procedure add a level of risk higher than the one of patients not undergoing 
embolization procedures. It is however believed based on data from 
previous case series and from expert opinion that the benefit of embolization 
will greatly outweigh the risks. 
GCP Statement 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP, the HRA as well as 
other locally relevant legal and regulatory requirements.  
 
 
 
 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
10 
 
2 
BACKGROUND AND RATIONALE  
Chronic Subdural Hematoma (cSDH) is one of the most frequently encountered pathologies in 
neurosurgery, presenting typically in the elderly population. The condition is often preceded by a 
history of a relatively minor trauma to the head, usually weeks before the onset of neurological 
symptoms. Patients can present with a wide set of neurological symptoms which typically include 
a reduced state of consciousness and confusion. The most important risk factors associated with 
cSDH development include anti-thrombotic medication use, male sex and craniocephalic 
disproportion often as a consequence of alcohol abuse, cerebral atrophy or both (1). Treatment 
for cSDH is typically undertaken once a patient becomes symptomatic and is classically 
performed by burr hole drainage of the hematoma, which resolves symptoms in a relatively rapid 
fashion.  
 
cSDH are known for their frequent recurrence, with estimates in literature currently approximating 
a rate of between 9-33% (2-5). While the exact pathophysiology of the initial hematoma formation 
is not fully understood, it is believed that the shearing of veins at the dural cell layer is the initiating 
event, neovascularization in the ensuing inflammatory response is thought to be nourished by 
branches of the middle meningeal artery (MMA) (1). As a consequence, recent studies have 
shown that the embolization of the MMA can result in lower rates of recurrence, with a recent 
systematic review showing a composite recurrence rate of only 3.6% (6). The ramifications of 
such a drastic decline in rates of recurrence include a reduced need to re-operate individuals, 
often elderly, who often require anti-thrombotic medication for other medical conditions. However, 
evidence to support the benefit of MMA embolization remains limited and the risk-benefit balance 
remains unclear. The potential efficacy of MMA embolization as a treatment therefore requires 
higher level evidence in the form of randomized control trials.  
 
In the present study, we outline the research protocol for a prospective multicenter randomized 
control trial wherein patients who undergo surgical treatment for cSDH will either receive post-
operative MMA embolization or will be under observation following conventional management. It 
is hypothesized that MMA-embolization will reduce the recurrence of cSDH.  
 
As a second focus, this study will also assess the potential benefit of MMA embolization for 
patients who have a surgical indication but cannot undergo surgery (due to personal or medical 
reasons). The objective of assessment of this cohort is to evaluate the capacity of MMA 
embolization to stop progression of cSDH. These patients as well as those choosing no treatment 
will not be randomized, but followed in the same manner as randomized patients. In this group it 
is hypothesized that MMA-embolization will prevent progression of the cSDH. 
3 
STUDY OBJECTIVES AND DESIGN  
2.1 Hypothesis and primary objective 
It is hypothesized that post-operative MMA embolization will reduce the recurrence of cSDH.  
 
The primary objective is to evaluate the recurrence rates of cSDH at 6 months after combined 
surgical and MMA embolization treatment (Arm 2) versus surgery without embolization (Arm 1) 
(Appendix 1).  
 
This study will also assess the potential benefit of MMA embolization-only treatment for patients 
who have a surgical indication but cannot undergo surgery (due to personal or medical reasons, 
Arms 3). The objective of assessment of this cohort is to evaluate the capacity of MMA 
embolization to stop progression of cSDH. These patients as well as those choosing no treatment 
(Arm 4) will not be randomized, but followed in the same manner as randomized patients (Arms 
1 and 2). In this group it is hypothesized that MMA embolization will prevent progression of the 
cSDH. For patients included in the Arms 3 and 4, the follow-up schedule remains the same as for 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
11 
 
the randomized cohort (Arms 1 and 2) (Appendix 2). Likewise, the same radiological parameters 
will be assessed (electronic Case Report Form (eCRF), Appendix 3). The second objective of our 
study is to evaluate the stability and regression of cSDH between all Arms of the study at follow-
up. 
 
2.2 Primary and secondary endpoints. 
 
Primary endpoint: The primary endpoint is cSDH recurrence at 6 months post-treatment. A 
recurrence is defined as a cSDH recurrence that requires surgical re-operation, a neurological 
deterioration due to a cSDH occurring 72 hours post-evacuation (or embolization) or thereafter, 
or a post-operative hematoma volume of more than 90% of the pre-operative volume at any 
follow-up.  
 
The study will use a combination of clinical, radiological and functional measures to assess 
differences in recurrence between the primary objective, and secondary objectives. The 
radiological assessment includes hematoma volume, maximal coronal and sagittal hematoma 
size, and degree of mid-line shift for unilateral cSDHs, as measured on CT at 6-weeks and 6-
months follow-up (Appendix 3). Recurrence of unilateral and bilateral hematomas will be 
recorded.  
 
Radiological definition of hematoma “regression”, “stability” and “progression” are defined as 
>10% reduction in hematoma volume, +/-10% of previous hematoma volume, >10% increase in 
hematoma volume, respectively. Furthermore, the presence and proportion of “acute” 
components of the hematoma will be noted (acute component of >75%, 50-75%, <50% and 
>25%, 25% or less,0%) (Appendix 3). 
 
Secondary endpoints: Additional outcomes such Glasgow Coma Scale (GCS), modified 
Ranking Scale (mRS), Markwalder Grading Scale (MGS), Glasgow Outcome Scale – Extended 
(GOS-E), Karnofsky Performance Score (KPS) and the Therapy-Disability-Neurology grading 
system (TDN) will be recorded (7-11) (Appendix 3). The occurrence of mortality and re-admission 
will likewise be monitored during the study period (Appendix 3). The recommencement of anti-
thrombotic medication for patients under such treatment will be noted at time of discharge, and 
each follow-up period (Appendix 3). 
2.3 Study design  
We plan on recruiting all adult patients based on the inclusion and exclusion criteria outlines in 
Appendix 1. Patient demographic characteristics will be collected, as well as notable 
comorbidities (including COVID infection), the use of steroids, use of antithrombotic medication, 
smoking status, alcohol abuse, history of trauma, COVID vaccination status (and time of 
vaccination) (Appendix 3). In addition, a Charleston comorbidity index score will be attributed to 
all patients (7) (Appendix 3).  
 
The study will be undertaken at the HUG and in the Lugano Neurocenter of the Southern 
Switzerland, and will in the future involved others trauma centres in Europe with the objective to 
enrol patients within an 18-24-month time-frame. With the last follow-up planned at 6-months, the 
combined study duration is expected to be no longer than 24-30 months. 
 
Patients who undergo surgical treatment will be randomized into receiving embolization within 72 
hours of surgery (Arm 2) or no-embolization (Arm 1) (Appendix 1). Patients will be randomized at 
rate of 2 MMA embolization to 1 conventional management. Depending on whether the consent 
can be obtained before surgery, and on the availability of neuro-interventional and anaesthesia 
staff, efforts will be made to undertake the embolization directly after surgery to avoid additional 
anaesthesia. 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
12 
 
The choice for the randomisation rate of 2 MMA embolisation / 1conventional management is 
based on the three following points: 
1) While there are no previous RCTs for this treatment, evidence seems to point to a consistent 
benefit of embolization with a low associated risk of complications. 
2) As MMA embolisation is a relatively new procedure, allocating more patients to the intervention 
reduces the potential effect of the learning curve on the results. 
3) As complications are rare, having more patients receiving MMA embolization permit to better 
evaluate this treatment. 
Patients who are excluded for surgery due to significant medical contraindications (e.g. severe 
thrombocytopenia or double anti-thrombotic therapy without imminent danger of death) or patients 
who refuse surgery will be considered for embolization only (Arms 3 and 4) (Appendix 1). 
2.4 Study intervention 
Patients who undergo surgical treatment will be randomized into receiving embolization within 72 
hours of surgery (Arm 2) or no-embolization (Arm 1). Patients will be randomized at rate of 2 MMA 
embolization to 1 conventional management. 
 
Patients who are excluded for surgery due to significant medical contraindications (e.g. severe 
thrombocytopenia or double anti-thrombotic therapy without imminent danger of death) or patients 
who refuse surgery will be considered for embolization only (Arms 3 and 4). 
 
The details of study intervention are shown in the Appendix 1 and in the schedule assessments 
(Appendix 2).  
4 
STUDY POPULATION AND STUDY PROCEDURES 
3.1 Inclusion and exclusion criteria, justification of study population 
Inclusion Criteria (Appendix 1):  
- 
Age 18-100 years, male or female 
- 
Consent possible 
- 
cSDH located at the convexities 
- 
Patients with symptomatic cSDH 
- 
Patients with asymptomatic large chronic/subacute hematoma after 6 weeks of failed 
conservative treatment. 
 
Exclusion Criteria (Appendix 1):   
- 
Consent not possible 
- 
Pregnancy 
- 
Prisoner 
- 
Angiography contraindication 
- 
Patient for whom follow-up is problematic (e.g. distant residency, homeless) 
- 
Previous surgery for cSDH 
 
Patients who will undergo surgical treatment (standard treatment of cSDH) and who will accept 
the STORMM consent will be randomized into receiving embolization within 72 hours post-
surgery (Arm 2) or no-embolization post-surgery (conventional management, Arm 1). Patients will 
be randomized at rate of 2 MMA embolization to 1 conventional management. 
 
Patients who are excluded for surgery, due to significant medical contraindications (e.g. severe 
thrombocytopenia or double anti-thrombotic therapy without imminent danger of death) or patients 
who refuse surgery, and who will accept the STORMM consent, will be considered for 
embolization only. Patients consenting embolization will be part of the Arm 3, and patients 
refusing embolization will be part of the Arm 4. 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
13 
 
3.2 Recruitment, screening and informed consent procedure 
We will proceed to a prospective recruitment in the Departments of Neurosurgery of the HUG and 
of the Lugano Neurocenter of the Southern Switzerland. All patients with inclusion criteria 
compatible will be enrolled for the different arms. 
 
The investigators and research personnel will explain to each participant (or their caretaker) the 
nature of the study, its purpose, the procedures involved, the expected duration, the potential 
risks and benefits, and any discomfort it may entail. Each participant (or their caretaker) will be 
informed that the participation in the study is voluntary and that he or she may withdraw from the 
study at any time and that withdrawal of consent will not affect his or her subsequent medical 
assistance and treatment.  
 
The participant (or their caretaker) will be informed that his or her medical records may be 
examined by authorised individuals other than their treating physician. 
 
All participants (or their caretaker) for the study will be provided a participant information sheet 
and a consent form describing the study and providing sufficient information for participant to 
make an informed decision about their participation in the study (Appendix 4 and 5). Patients (or 
caretaker) will be given at least 24 hours to decide whether to participate or not. However, patients 
can be included if they wish to give their consent before 24 hours. The formal consent of a 
participant, using the approved consent form, will be obtained before the participant is submitted 
to any study procedure (Appendix 4). In case of patient without discernment, the consent form 
could be signed by his/her representative (Appendix 5). The consent form will be signed and 
dated by the investigator or his/her designee at the same time as the participant sign. A copy of 
the signed informed consent will be given to the study participant. The consent form will be 
retained as part of the study records. 
 
In case of emergency, if MMA embolization can be performed directly following the surgery, as 
this would reduce the risk associated with undergoing a second anaesthesia for the embolization 
sometime after the surgery, the patient could be recruited in emergency (Appendix 6 and 7). The 
anaesthesiologist involved in the care of the patient, but not involved in the project, will be 
consulted before the emergency inclusion of the patient in the study. The consent of the patient 
(Appendix 6) or of her/his legal representative (Appendix 7) will be requested a posteriori. If the 
patient or her/his legal representative refuses consent, the patient's data will not be included in 
the study. 
 
Patients who decide not to participate in the study will be treated as per current standard of care. 
3.3 Study procedures 
The study will be undertaken at the HUG and in the Lugano Neurocenter of the Southern 
Switzerland, and will in the future involved others trauma centres in Europe with the objective to 
enrol patients within an 18-24-month time-frame. With the last follow-up planned at 6-months, the 
combined study duration is expected to be no longer than 24-30 months.Patients who undergo 
surgical treatment will be randomized into receiving embolization within 72 hours post-surgery 
(Arm 2) or no-embolization (Arm 1). Patients will be randomized at rate of 2 MMA embolization to 
1 conventional management. 
Patients who are excluded for surgery due to significant medical contraindications (e.g. severe 
thrombocytopenia or double anti-thrombotic therapy without imminent danger of death) or patients 
who refuse surgery will be considered for embolization only: Arm 3: Patients consenting 
embolization; Arm 4: Patients refusing embolization. 
3.4 Withdrawal and discontinuation 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
14 
 
Patients will be able to withdraw from the study at any given time by notifying the investigators 
(Appendix 8 and 9). Patients will have to choose whether she/he wants that her/his data will 
be stored coded or anonymized. Anonymised information regarding patients’ sex and age will 
be kept in a separated, encoded file to test for selection biases (internal quality control of the 
study). 
 
5 
STATISTICS AND METHODOLOGY 
4.1. Statistical analysis plan and sample size calculation 
Randomized Arms: Arms 1 and 2:  
The incidence rates of cSDH recurrence is estimated at 20% and 5% without and with MMA 
embolization, respectively. For an alpha = 0.05 and a power of 80%, we estimate that a minimum 
of 156 patients need to be enrolled. Assuming a 15% loss of follow-up, a total of 180 patients 
need to be enrolled in the study. It is therefore planned to enrol 180 patients. 
 
Comparison of recurrence rate between the groups will be assessed via logistic multivariate 
analysis where recurrence is the dependent variable. Sex, presence of unilateral/bilateral cSDH, 
treatment of anti-thrombotic medication, alcohol abuse, age and cerebral atrophy will be 
considered as independent variables. 
 
The random assignment of participants to conventional treatment (Arm 1) or MMA embolization 
(Arm2) will be achieved using a block randomization method stratified by centre (Geneva, 
Lugano). Random block sizes will be used. To maintain the concealment of allocation principle, 
block sizes will only be revealed once enrolment is ended. 
For each centre, the randomization list will respect a 1:2 ratio (1 conventional management for 2 
MMA embolization). Expecting a higher capacity of patient enrolment in Geneva, the 
randomization lists will be of different size: 
- 
The randomization list will be of size n=120 in Geneva (n=40 in arm1, n=80 in arm2); 
- 
The randomization list will be of size n=60 in Lugano (n=20 in arm1, n=40 in arm2). 
Randomization will be computer generated with R software. The seed allowing to reproduce the 
randomization plan will be stored in the programming file of the software (r script). 
 
Embolization-only Arms: Arms 3 and 4: 
This part of the study is inherently exploratory, and it is not possible to estimate how many people 
will fall into this category as this is not yet a standardized treatment. The benefits of embolization 
(Arm 3) will be compared to patients who are eligible for embolization only but do not receive this 
treatment (the patient or his/her caregivers do not wish) and are only followed clinically (Arm 4). 
Enrolment for this portion of the study will terminate once the recruitment goal of the randomized 
portion of the study is attained. If the cohort size permits, changes in outcomes (changes in 
volume progression, mortality and readmission) between these 2 groups will be assessed with 
univariate and multivariate analysis. 
4.2. Handling of missing data and drop-outs 
Data obtained until the dropout will be kept unless the patient refuses. If interpretable, they will 
be analysed. Missing data will not be imputed or replaced; patients with missing data will be 
excluded from analyses for the primary objectives, however, this data may be used for 
subsequent secondary analyses if interpretable. 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
15 
 
6 
REGULATORY ASPECTS AND SAFETY 
5.1 Local regulations / Declaration of Helsinki 
This study is conducted in compliance with the protocol, the current version of the Declaration of 
Helsinki, the ICH-GCP, the HRA as well as other locally relevant legal and regulatory 
requirements (12-17).  
5.2 (Serious) Adverse Events and notification of safety and protective measures 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation 
subject which does not necessarily have a causal relationship with the trial procedure. An AE can 
therefore be any unfavorable or unintended finding, symptom, or disease temporally associated 
with a trial procedure, whether or not related to it. 
 
A Serious Adverse Event (SAE) (ClinO, Art. 63) is any untoward medical occurrence that 
- 
Results in death or is life-threatening, 
- 
Requires in-patient hospitalization or prolongation of existing hospitalization, 
- 
Results in persistent or significant disability or incapacity, or 
- 
Causes a congenital anomaly or birth defect. 
 
Both Investigator and Sponsor-Investigator make a causality assessment of the event to the trial 
intervention (see table below based on the terms given in ICH E2A guidelines (16)). Any event 
assessed as possibly, probably or definitely related is classified as related to the trial intervention. 
 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above 
conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Both Investigator and Sponsor-Investigator will make a severity assessment of the event as mild, 
moderate or severe. Mild means the complication is tolerable, moderate means it interferes with 
daily activities and severe means it renders daily activities impossible.  
 
Reporting of SAEs (see ClinO, Art. 63) 
All SAEs will be documented and reported immediately (within a maximum of 24 hours) to the 
Sponsor-Investigator of the study (Appendix 10). 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
16 
 
If it cannot be excluded that the SAE occurring in Switzerland is attributable to the intervention 
under investigation, the investigator will report it to the Ethics Committee via BASEC within 15 
days. 
If the SAE occurs at one of the study sites, the coordinating investigator will report the events to 
the Ethics Committee concerned, within 15 days. 
 
Follow up of (Serious) Adverse Events  
The patient population on average is considered very old (70-80 years) and present with a 
condition requiring surgery. Therefore, the possibility of SAE regardless of embolization is 
considered high. We will note the record cases of mortality, re-operation within 6 months, and 
embolization related complications, and undertake an interim analysis after 50% of study 
enrollment. As this would result in an estimated 60 patients (30 of 90 enrolled) receiving 
embolization, this number will likely provide sufficient to determine if there is a significant increase 
of adverse events. Monitoring for adverse events will be undertaken continuously, and if it is 
deemed that there is a disproportionate number of adverse events that are occurring prior to the 
interim analysis, an earlier case-analysis may be sought under such an exceptional circumstance. 
The management of and reporting of adverse events will be guided by the center of clinical 
research at HUG. 
 
Notification of safety and protective measures (see ClinO, Art 62, b) 
If immediate safety and protective measures have to be taken during the conduct of the study, 
the investigator will notify the Ethics committee of these measures, and of the circumstances 
necessitating them, within 7 days. 
5.3 (Periodic) safety reporting 
An annual safety report (ASR/DSUR) will be submitted once a year to the local Ethics Committee 
by the Investigator (ClinO, Art. 43 Abs). In international multicentric studies, the ASR/DSUR 
contains information from all sites including information from sites outside of Switzerland. The 
Sponsor-Investigator distributes the ASR/DSUR to all the participating Investigators.  
5.4 Radiation 
The radiation exposure from conventional cerebral angiograms has been reported to range 
between 350 to 4100 mGy, with the wide range being due to numerous factors including body 
habitus, anatomy and technical factors (18). This dose in the context of radiology is high and 
the risks and benefits of the neuro-interventional procedure which includes radiation 
exposure will be discussed as part of the standard consent practices. 
5.5 Pregnancy (if applicable) 
Pregnant women are excluded from the present study. 
5.6 Amendments 
Substantial changes to the study setup and study organization, the protocol and relevant study 
documents will be submitted to the Ethics Committee for approval before implementation. Under 
emergency circumstances, deviations from the protocol to protect the rights, safety and well-being 
of human subjects may proceed without prior approval of the Ethics Committee. Such deviations 
shall be documented and reported to the Ethics Committee as soon as possible. 
 
A list of all non-substantial amendments will be submitted once a year to the competent EC 
together with the ASR. 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
17 
 
5.7 (Premature) termination of study 
The Sponsor-Investigator may terminate the study prematurely according to certain 
circumstances, e.g. 
- 
Ethical concerns, 
- 
Insufficient participant recruitment, 
- 
When the safety of the participants is doubtful or at risk (e.g. when the benefit-risk 
assessment is no longer positive), 
- 
Alterations in accepted clinical practice that make the continuation of the study unwise, 
- 
Early evidence of harm or benefit of the experimental intervention. 
 
Upon regular study termination, the Ethics Committee will be notified via BASEC within 90 days 
(ClinO, Art. 38). Upon premature study termination or study interruption, the Ethics Committee is 
notified via BASEC within 15 days (ClinO, Art. 38). 
 
At the end of the study, all health-related data and data analysis will be anonymized and will be 
kept in an encoded document available to the Principal Investigator during a duration of 10 years. 
5.8 Insurance 
In the event of study-related damage or injuries, the liability of the institution HUG provides 
compensation, except for claims that arise from misconduct or gross negligence.  
6 
FURTHER ASPECTS 
6.1 Overall ethical considerations 
The study protocol, the documents intended for the patients, and the list of investigators have 
been submitted to the Cantonal Commission of Ethics for Research on human beings (CCER) for 
approval. During the course of the study, the investigators will be obliged to submit to the CCER 
for review any changes to these documents, to inform the CCER of the progress of the study, of 
the occurrence of SAEs and of any new relevant facts concerning the investigational product. 
6.2 Risk-benefit assessment  
Evidence to support the benefit of MMA embolization remains limited and the risk-benefit balance 
remains unclear, although preliminary evidence seems to suggest a significant benefit. 
 
The potential efficacy of MMA embolization as a treatment therefore requires higher level 
evidence in the form of randomized control trials. 
 
7 
QUALITY CONTROL AND DATA PROTECTION 
7.1 Quality measures  
The interview of the patient will be done by a clinician of the clinical care team via the use of 
computerized data entry of the hospital’s patient records interface. 
 
Health-related personal data captured during this project are strictly confidential. Data generation, 
storage and analyses of health-related personal data within this project will strictly follow the 
current Swiss legal requirements for data protection and will be performed according to the 
Ordinance HRO Art. 5. Only authorized personnel will have access to health-related data. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Authorities. 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
18 
 
 
For quality assurance the sponsor, the Ethics Committee or an independent trial monitor may visit 
the research sites. Direct access to the source data and all study related files is granted on such 
occasions. All involved parties keep the participant data strictly confidential.  
7.2 Data recording and source data 
The investigators will manage the data which will be treated confidentially according to the rules 
of medical secrecy. The data of each patient will be reported in a dedicated eCRF (Appendix 3) 
and encoded. The same code will be assigned to the source data containing the patient’s 
parameters. The CRFs will be kept in the Neurosurgery Departments until the end of the study. 
For security and storage issues, data will be transcribed and coded in a REDCap database that 
will be created especially for this study. The principal investigator and secondary investigators will 
keep the code key. 
7.3 Confidentiality and coding 
Study data will be collected from the CRFs. Patient names will be replaced by a study participation 
number (code). Only investigators actively involved in the study will know the identity of the 
patient. Subjects will be informed that their personal data may be made available in the event of 
an audit or inspection by regulatory authorities, in a confidential manner and for the purpose of 
verifying the application of the ethical principles of Good Clinical Practice in the context of a 
research protocol. In case of publication, the results will be expressed in a collective manner and 
no patient will be identifiable.  
 
The type of coding is quantitative. Software used for coding and archiving will be the REDCap 
database, a swiss CTDMS (Clinical Trials Data Management system) already widely used in our 
institution. 
7.4 Retention and destruction of study data  
All study data are archived for 10 years after study termination or premature termination of the 
study. 
8  MONITORING AND REGISTRATION 
For the Geneva University Hospitals, the institution that will perform the monitoring duties of this 
study is the Clinical Research Center of the HUG (Appendix 11). 
 
Performed monitoring will be: 
- 
site initiation visit, 
- 
routine visit at 5% patient’s inclusion: full source data verification (SDV), 
- 
routine visit at 50% of remaining patients: partial SDV-key data, 
- 
close-out visit. 
For the Neurocenter of the Southern Switzerland, the institution that will perform the monitoring 
duties of this study is the Clinical Trial Unit of the EOC (Appendix 12). 
 
Performed monitoring will be: 
- 
site initiation visit, 
- 
Routine Monitoring Visit 1: Once 5 participants are enrolled, 
- 
Routine Monitoring Visit 2: Once 21-24 participants are enrolled,  
- 
Routine Monitoring Visit 3: Once 37-42 participants are enrolled, 
- 
Routine Monitoring Visit 4: Once 53 participants are enrolled - last visit of the 60th,  
- 
Routine Monitoring Visit 5: Once 69 participants are enrolled, 

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
19 
 
- 
Routine Monitoring Visit 6: Once 86 participants are enrolled, 
- 
Routine Monitoring Visit 7: Once 103 participants are enrolled, 
- 
Routine Monitoring Visit 8: After last participant last visit, 
- 
Close-Out Visit: After database lock except in case of premature site closure 
The study is registered in a national language in the Swiss National Clinical trial Portal (SNCTP 
via BASEC): SNCTP000005765 | NCT06163547 | BASEC2023-00848. In addition, the study is 
registered in a registry listed in the WHO International Clinical Trials Registry Platform (ICTRP; 
http://www.who.int/ictrp/en/): Clinicaltrials.gov: NCT06163547.  
9. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
The authors declare no competing interest.  
 
Currently the project is funded by the “Fond de Service de Neurochirurgie (HUG)”, and the 
“Fondation Privée des HUG”, and financial support are regularly submitted to private foundations 
and public funding agencies. 
 
Results will be disseminated via several ways:  
- Research reports for the financial supporting foundations, 
- Scientific article(s) in peer-reviewed international journal(s). 
 
All data or biological samples collected from patients in this study are public but remain protected 
and access gated under the responsibility of the HUG and the project leader. 
 
All data resulting from the processing of information remains the intellectual property of the 
individual or group of individuals that developed the data processing method and remain under 
the responsibility of the individual or group of individuals that generated the processed data. 
10. REFERENCES 
1. 
Nouri A, Gondar R, Schaller K, Meling T. Chronic Subdural Hematoma: A Review of the 
Current State of the Art. 2021. 
2. 
Torihashi K, Sadamasa N, Yoshida K, Narumi O, Chin M, Yamagata S. Independent 
predictors for recurrence of chronic subdural hematoma: a review of 343 consecutive surgical 
cases. Neurosurgery. 2008;63(6):1125-9. 
3. 
Pahatouridis D, Alexiou GA, Fotakopoulos G, Mihos E, Zigouris A, Drosos D, et al. 
Chronic subdural haematomas: a comparative study of an enlarged single burr hole versus 
double burr hole drainage. Neurosurgical review. 2013;36(1):151-5. 
4. 
Kolias AG, Chari A, Santarius T, Hutchinson PJ. Chronic subdural haematoma: modern 
management and emerging therapies. Nature Reviews Neurology. 2014;10(10):570-8. 
5. 
Nassiri F, Hachem LD, Wang JZ, Badhiwala JH, Zadeh G, Gladstone D, et al. 
Reinitiation of Anticoagulation After Surgical Evacuation of Subdural Hematomas. World 
Neurosurgery. 2020;135:e616-e22. 
6. 
Srivatsan A, Mohanty A, Nascimento FA, Hafeez MU, Srinivasan VM, Thomas A, et al. 
Middle meningeal artery embolization for chronic subdural hematoma: meta-analysis and 
systematic review. World neurosurgery. 2019;122:613-9. 
7. 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying 
prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 
1987;40(5):373-83. 
8. 
Markwalder TM, Steinsiepe KF, Rohner M, Reichenbach W, Markwalder H. The course 
of chronic subdural hematomas after burr-hole craniostomy and closed-system drainage. J 
Neurosurg. 1981;55(3):390-6. 
9. 
Karnofsky DA, Burchenal JH, Armistead GC, Jr., Southam CM, Bernstein JL, Craver LF, 
et al. Triethylene melamine in the treatment of neoplastic disease; a compound with nitrogen-

Service de Neurochirurgie 
Etude STORMM 2023-00848 
Version 2.0 25.09.2024 
 
20 
 
mustardlike activity suitable for oral and intravenous use. AMA Arch Intern Med. 
1951;87(4):477-516. 
10. 
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver 
agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-7. 
11. 
Jennett B, Snoek J, Bond MR, Brooks N. Disability after severe head injury: 
observations on the use of the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry. 
1981;44(4):285-93. 
12. 
Declaration of Helsinki. https://www.wma.net/policies-post/wma-declaration-of-helsinki-
ethical-principles-for-medical-research-involving-human-subjects/ 
13. 
Federal Act on Data Protection (FADP). https://www.admin.ch/opc/en/classified-
compilation/19920153/index.html 
14. 
Human Research Act (HRA). https://www.admin.ch/opc/de/classified-
compilation/20061313/index.html 
15. 
International Conference on Harmonization (ICH) E6(R2) Guideline for Good Clinical 
Practice. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__St
ep_4_2016_1109.pdf 
16. 
International Conference on Harmonization (ICH) E2A Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5000
02749.pdf 
17. 
Ordinance on Clinical Trials in Human Research (ClinO). 
https://www.admin.ch/opc/de/classified-compilation/20121176/index.html  
18. 
Pearl MS, Torok C, Wang J, Wyse E, Mahesh M, Gailloud P. Practical techniques for 
reducing radiation exposure during cerebral angiography procedures. Journal of 
neurointerventional surgery. 2015;7(2):141-5. 
 
 
APPENDIX 
 
Appendix 1: Inclusion and exclusion criteria - Study arms 
Appendix 2: Schedule of assessment 
Appendix 3: Case report form 
Appendix 4: Information letter and informed consent form for patients 
Appendix 5: Information letter and informed consent form for representative 
Appendix 6: Information letter and informed consent form for patients recruited in emergency 
Appendix 7: Information letter and informed consent form for representative of patients recruited 
in emergency 
Appendix 8: Consent withdraw for patients 
Appendix 9: Consent withdraw for representative 
Appendix 10: SAE report 
Appendix 11: Monitoring plan for Geneva 
Appendix 12: Monitoring plan for Lugano