Enhanced Recovery Pathway for Chronic Subdural Hematoma
Conditions: Chronic Subdural Hematoma, Chronic Subdural Hematomas
Sponsor: Universitaire Ziekenhuizen KU Leuven

Version 2.0_01Sept2024  
Page 1 of 18                                        Protocol ERP-cSDH 
                                                                                     
   
 
 
 
 
 
 
 
PROTOCOL FOR AN OBSERVATIONAL STUDY 
 
Enhanced 
Recovery 
Pathway 
for 
Chronic 
Subdural 
Hematoma 
ERP-cSDH 
Version number: v 2   –  Date 1/09/2024 
 
Internal ref. nbr:  S68819 
Sponsor 
University Hospitals Leuven (UZ Leuven) 
Herestraat 49, B-3000 Leuven 
 
 
 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 2 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
LIST OF PARTICIPATING SITES 
 
List Of Participating Sites 
UZ Leuven, Herestraat 49, 3000 Leuven 
 
 
 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 3 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
TABLE OF CONTENTS 
LIST OF PARTICIPATING SITES ........................................................................................ 2 
SIGNATURES ............................................................... Fout! Bladwijzer niet gedefinieerd. 
TABLE OF CONTENTS ........................................................................................................ 3 
FUNDING AND SUPPORT .................................................................................................. 4 
ROLES AND RESPONSIBILITIES ....................................................................................... 4 
STUDY SYNOPSIS .............................................................................................................. 5 
1. 
Background and Rationale ............................................................................................ 7 
2. 
Study Objectives and Design ......................................................................................... 7 
2.1 
Study objectives ..................................................................................................... 8 
2.2 
Primary Endpoints .................................................................................................. 8 
2.3 
Secondary Endpoints ............................................................................................. 8 
2.4 
Study Design .......................................................................................................... 9 
2.5 
Expected duration of the study ............................................................................. 10 
2.6 
Translational research ..................................... Fout! Bladwijzer niet gedefinieerd. 
3. 
Study Population / Eligibility Criteria ............................................................................ 10 
3.1 
Inclusion criteria ................................................................................................... 10 
3.2 
Exclusion criteria .................................................................................................. 11 
4. 
Assessment of Efficacy ............................................................................................... 11 
5. 
Assessment of Safety .................................................................................................. 11 
5.1 
Specification, timing and recording of safety parameters ...................................... 11 
5.2 
Treatment stopping rules ...................................................................................... 11 
6. 
Statistics and Data Analysis ........................................................................................ 12 
7. 
Data handling .............................................................................................................. 12 
7.1 
General data handling information ........................................................................ 12 
7.2 
Study specific data handling information ............................................................... 13 
8. 
Ethical and Regulatory Considerations ........................................................................ 14 
8.1 
Ethics Committee (EC) review & reports ............................................................... 14 
8.2 
Protocol / GCP compliance................................................................................... 14 
8.3 
Data protection and participant confidentiality ...................................................... 14 
9. 
Research Registration, Dissemination of Results and Publication Policy ..................... 15 
10. 
Insurance/Indemnity ................................................................................................. 15 
11. 
References .............................................................................................................. 15 
 
 
 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 4 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
FUNDING AND SUPPORT 
Funder 
Type of Financial or Non-Financial Support 
Departement of Neurosurgery, 
UZ Leuven 
Financial support for study set-up, data management program 
and statistical support 
 
 
 
 
 
 
ROLES AND RESPONSIBILITIES 
The Principal Investigator (PI) is responsible for the conduct of the Study at his/her Participating Site, 
and for protecting the rights, safety and well-being of Study participants. As such the PI must ensure 
adequate supervision of the Study conduct at the Participating Site. If any tasks are delegated, the PI 
will maintain a log of appropriately qualified persons to whom he/she has delegated specified Study-
related duties. The PI will ensure that adequate training is provided and documented for all Study 
staff, prior to conducting assigned Study-related activities. Even when certain activities are 
delegated, the PI will ultimately remain responsible for the conduct of the Study at his/her 
Participating Site. 
It is the Coordinating Investigator's (CI’s) responsibility to supervise the general conduct (e.g. Study 
progress, communication, protocol training and support of the participating sites, annual reporting 
to the Ethics Committee (EC), end of Study notification(s) and results reporting…) of the Study. The 
CI fulfils both Investigator and Sponsor responsibilities, as outlined in International Conference on 
Harmonisation – Good Clinical Practice (ICH-GCP) E6(R2) and applicable regulations. 
PI and CI shall each be referred to as «Investigator(s)». 
 
 
 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 5 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
STUDY SYNOPSIS 
 
Title of clinical Study 
(«Study») 
Enhanced Recovery Pathway for Chronic Subdural Hematoma 
Protocol Short Title 
Acronym 
ERP-cSDH 
Sponsor name 
University Hospitals Leuven (UZ Leuven)> 
Medical 
condition 
or 
disease under investigation 
Chronic subdural hematoma 
Study rationale  
 
A chronic subdural hematoma (cSDH) is a type of intracranial 
hematoma that primarily affects older adults. The rising incidence of 
this condition, coupled with the high healthcare burden of this 
disease, calls for an update of the medical care program. We 
introduced an enhanced recovery protocol (ERP) at our center for 
patients undergoing treatment for a chronic subdural hematoma. Our 
ERP includes guidelines for treatment decisions (surgery or middle 
meningeal artery embolization - MMA), modifications in surgical 
techniques, and standardized postoperative management strategies. 
Prospective analysis of the treatment outcomes is vital. 
Primary objective 
 
Analysing the safety and efficacy of an enhanced recovery protocol 
for patients undergoing burr hole drainage of a chronic subdural 
hematoma. Safety and efficacy outcomes will be compared with the 
outcomes of a historical patient cohort. Safety of the protocol will be 
measured in terms of recurrence rate (primary outcome, non-
inferiority analysis), complication incidence, and 30-day mortality. 
Efficacy of the enhanced recovery protocol will be represented by 
the length-of-stay. 
Secondary objective(s) 
A separate analysis will be performed measuring the difference in 
treatment related costs between the historic treatment protocol and 
the enhanced recovery protocol. 
Trial Design 
Non-interventional, prospective, non-inferiority trial 
Sample size  
Prospective patient cohort: 150 subjects 
Retrospective patient cohort: all eligible consecutive patients treated 
by burr hole drainage between 2012-2022 
Maximum duration a 
research subject remains in 
the study 
6 months 
Participating research sites 
University Hospitals Leuven (UZ Leuven) 
Third parties 
None 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 6 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
 
 
 
 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 7 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
1. Background and Rationale   
  Briefly explain the background, issues and medical relevance of the study. Make a convincing case as to why 
the study would create valuable and useful scientific knowledge, what the expected benefits and risks are, and the 
rationale as to why it is expected that this Study will have a positive benefit/risk balance. 
 
A chronic subdural hematoma (cSDH) is a type of intracranial hematoma that occurs mainly in older 
adults, and which is pathogenically characterized by the slow accumulation of blood between the 
cerebral cortex and the dura mater. Clinical manifestations of a cSDH vary depending on the size of 
the hematoma and the extent to which it compresses different parts of the brain, although common 
features include headache, limb weakness, mental disorders, and epilepsy. The process of cSDH 
formation and progression remains poorly understood, and possible explanatory hypotheses include 
subclinical brain injury causing bridging vein trauma, inflammatory responses, transformation of an 
acute subdural hematoma, osmotic pressure gaps, and neovascularization of leaky vessels in the 
subdural membrane.1 At present, the most common treatment strategy for a cSDH involves surgical 
drainage of the hematoma, although lately endovascular treatment is gaining popularity. 
Endovascular embolization of the middle meningeal artery (MMA) impedes neovascularisation of 
highly permeable dural vessels and has been shown to reduce hematoma volume.2 The exact part of 
this novel treatment modality in the treatment of cSDH patients remains rather uncertain. 
The estimated yearly incidence of CSH ranges from 8.2 to 20.6 per 100.000, but in the age group over 
65 this rises to 58 per 100 000 per year, which makes it one of the most prevalent neurosurgical 
conditions.3, 4 The burden of cSDH is even projected to increase in the decades ahead due to the 
growing elderly population and the widespread use of antithrombotic agents, which are believed to 
promote hematoma formation.5, 6 A cSDH has been described as a ‘sentinel health event’ indicating 
underlying systemic pathology, because it has a 1-year mortality similar to that of hip fractures.7 
There are still major challenges in cSDH treatment. The risk of recurrence after treatment is high. 
Hematoma recurrence causes repeated intervention, leading to prolonged hospital stays, higher 
morbidity, mortality, and healthcare costs.8 In the literature, the recurrence ratio ranges from 3 to 
33%.9-11 In UZ Leuven, there were 13 cases of recurrence on 119 procedures (10,9%) that were 
performed in the adult population between 01-01-2019 and 31-08-2022. Other challenges are the lack 
of sufficient class I evidence describing the optimal surgical and perioperative management, overload 
of conflicting evidence concerning treatment, uncertainty of optimal antithrombotic withdrawal 
interval and lack of multidisciplinary healthcare pathways in the elderly.12 
The increasing incidence of this pathology together with its high healthcare burden calls for an update 
of the medical care program in order to decrease disease-related morbidity and costs. We introduced 
an enhanced recovery program (ERP) in our centre for patients undergoing surgery for a chronic 
subdural hematoma. An ERP can be defined as a series of evidence-based practices covering all 
aspects of perioperative care, serving to minimize the patients’ surgical stress response, facilitate 
recovery and decrease complication incidence.  

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 8 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
Elderly patients stand to benefit from minimally invasive treatments given their advanced age and 
subsequent increased rate of comorbidities and surgical risk factors. An integrated approach to care 
in patients with a cSDH, similar to care of fragility fractures in the elderly, may be an important 
strategy to improve patient care and outcomes.7 Our ERP-care pathway comprises of treatment 
decision guidelines (surgery and/or MMA), changes in surgical techniques and standardized 
postoperative management strategies.  
 
2. Study Objectives and Design 
2.1 Study objectives 
  State the purpose of the study (i.e. aims and objectives). Describe the primary research question, and define a 
specific hypothesis. See also: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002877.pdf   
The primary aim of this study is to evaluate the efficacy and safety of our ERP in patients undergoing 
surgical drainage of a chronic subdural hematoma. We hypothesize that the implementation of an 
enhanced recovery pathway will result to a lower in-hospital complication incidence and length of 
stay without increasing hematoma recurrence rate.  
Secondary aim:  
A separate analysis will be performed measuring the difference in treatment related costs between 
the historic treatment protocol and the enhanced recovery protocol.2.2 Primary 
Endpoints 
  Define specific parameters that will be assessed to achieve the primary objective (i.e. specific hypothesis) of the 
study. These are the datapoints that will be collected in the study-specific Case Report Form (CRF). 
The primary outcome will be recurrence rate assessed at 6 months after index surgery. Recurrence is 
defined as persistent deficits, clinical deterioration or radiographic hematoma enlargement requiring 
ipsilateral re-intervention (surgical or by means of MMA). In case of bilateral hematomas, a unilateral 
recurrence would suffice to be recorded as a recurrence. A second recurrence will not be included in 
the analysis. 
2.3 Secondary Endpoints 
  Define parameters that will be assessed. These are the datapoints that will be collected in the study-specific 
Case Report Form (CRF). 
Secondary outcomes are: 
-  Length of stay (LOS) after surgery 
- Complication incidence. Complications will be classified as medical complications (any nonsurgical 
complication occurring during the hospital stay after the surgery) and surgical complications. Medical 
complications are considered minor if complete recovery is to be expected (eg, electrolyte 
disturbances or urinary tract infection) and major in case of potential serious consequences and 
partial or no recovery (eg, stroke, severe pneumonia, or pulmonary embolism). Surgical complications 
are defined as every complication directly related to the surgery. Epileptic seizures in the 
postoperative period will be considered separately. 
- Total costs of hospital admission 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 9 of 18                                        Protocol template for observational                               
                                                                                    Confidential & Proprietary                                                clinical research study  
- 30-day mortality 
2.4 Study Design 
  Describe the design of the research study. 
We will conduct a single-centre, prospective, non-interventional cohort study in patients treated for 
a chronic subdural hematoma at University Hospitals Leuven (Belgium). An enhanced recovery 
pathway (ERP) for chronic subdural hematoma patients was developed in conjunction with the 
department of neuroanaesthesiology and neurosurgery. The ERP is gradually being implemented as 
new standard of care. The ERP consists of guidelines for treatment modality (surgery or MMA), 
modifications in surgical techniques, and standardized postoperative management strategies (cfr. 
Supplemental content). All consecutive patients with a chronic subdural hematoma requiring burr 
hole evacuation will be included for analysis. Study participants with bilateral cSDH will be included as 
a single study participant.  
For the primary analysissafety, efficacy, and costs outcomes of patients treated with burr hole 
drainage after ERP-implementation will be compared with outcomes of a historic cohort of the pre-
ERP era. This historic cohort will retrospectively be assessed and comprises of all consecutive adult 
patients who underwent burr hole drainage between January 2012 and December 2022. In this 
timeframe, treatment regime for cSDH patients was not subjected to change. The patient data of the 
historic cohort will be extracted from electronic patient files. Patients treated during the transition 
period (January 2023 to September 2024) will be neglected for analysis. Safety outcomes comprise of 
recurrence rate (primary outcome), complication incidence and 30-day mortality. Efficacy of the 
protocol will be measured through length-of stay. Non-inferiority of the ERP-protocol in comparison 
to the historic cohort will be analysed for the primary outcome. 
Outcome data for our prospective cohort will clinically be assessed at hospital discharge, clinically and 
radiologically at 4-6 weeks and clinically 6 ± 1 months after treatment. Furthermore, an EQ-5D-5L 
questionnaire will be provided at baseline and at 6 ± 1 months after treatment. At 6 ± 1 months after 
treatment a short satisfaction survey will also be added. These questionnaire will be provided through 
the secure environment of nexuzhealth (through the app, quest on tab, on paper or through a safe 
link in an email). Reminders will be programmed and sent out if questionnaires are not completed. A 
baseline questionnaire will be filled in by the patient or by the relatives at the moment of the informed 
consent and inclusion in the study. 
 
Trial flowchart 
 
Screening 
Baseline 
Interventio
n 
(surgery/M
MA) 
Hospital 
discharge 
FU clinical  
(4-6 weeks; 
SoC) 
FU clinical  
(6 ± 1 
months ; 
SoC) 
Check in-and 
exclusion criteria 
x 
 
 
 
 
 
Informed consent 
 
x 
 
 
 
 
Demographic 
data 
 
x 
 
 
 
 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 10 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
Neurological 
status (NIHSS, 
mRS, Markwalder 
score13), seizures, 
antitrombotic 
medication use  
 
x 
 
 
x 
x 
Hematoma 
characteristics on 
CT-imaging 
 
x 
 
 
x 
 
Intraoperative 
variables 
(operation 
duration, uni-or 
bilateral surgery, 
catheterisation 
technique and 
material) 
 
 
x 
 
 
 
Duration of 
catheter 
presence, length 
of stay, hospital 
costs 
 
 
 
x 
 
 
Readmissions, 30-
day mortality, 
complications, 
and seizures 
 
 
 
 
x 
x 
PROM’s (EQ-5D-
5L) 
 
x 
 
 
 
x 
2.5 Expected duration of the study 
  Specify the expected duration and define the end of the study for the study participants. This can be the full 
study duration e.g. first patient first visit to last patient last visit including follow up. Alternatively, for long running 
studies (e.g. oncology), the end of study can be defined at a specific time point at which the study will be regarded 
as completed even if participants are still in follow up. A simple table format or timeline is the preferred style. Make 
the distinction between the expected overall study duration for the research site(s) and the expected study duration 
for a single participant..  
Patients can be included in the trial as soon as surgery is scheduled. Study will end after the clinical 
follow-up at 6 ± 1 months after intervention. 
2. Study Population / Eligibility Criteria 
3.1 Inclusion criteria 
  List details under which a participant is considered eligible for inclusion in the study. 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 11 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Age 18 years or older 
2. Existence of a chronic subdural hematoma requiring burr hole drainage  
3. Written informed consent to participate in the study must be obtained from the subject. If 
the subject is not capable of self-consent, all efforts will be made to locate a legally acceptable 
representative to act on behalf of the subject. When the patient is considered capable to 
consent but physically unable to sign an informed consent form and a representative is not 
available an impartial witness can attend the informed consent process. 
3.2 Exclusion criteria 
. List details under which a participant is considered unsuitable for inclusion in the study 
Participants eligible for this study must not meet any of the following criteria: 
1. Acute subdural hematoma 
2. Existence of an important underlying cerebral lesion (e.g. a vascular lesion) 
3. History of treatment (surgical or by MMA) of a same sided cSDH  
4. Assessment of Efficacy 
  Describe the measures that will be used to determine the efficacy of treatment (eg glucose, blood pressure, 
tumour reduction etc). Primary efficacy parameters should be stated first, then any secondary parameters (may 
already have been described in the study design) 
The efficacy of an enhanced recovery pathway can be assessed either by analysing pathology-specific 
outcomes measures or by outcome measures related to the efficacy of the care pathway. Efficacy 
assessment will be performed by comparing recurrence rate, complication incidence, 30-day mortality 
and length-of stay of the ERP-cohort with the pre-ERP cohort.  
5. 
Assessment of Safety 
  Describe the measures that will be used to determine subject safety during the study. These will include physical 
examination, blood tests and adverse event reporting 
5.1 
Specification, timing and recording of safety parameters 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the treatment pathway. During hospitalisation, daily clinical 
examinations will be performed as part of standard of care to assess patient status. To assess safety 
of our new care pathway complications (surgical and medical complications), 30-day mortality rate 
and hematoma recurrence will be strictly monitored. No interim analyses are scheduled. 
Since this is a non-interventional observational study comparing a new standard of care with a historic 
treatment strategy, inclusion in this study does not impose any patient’s risk.  
 
5.2 
Treatment stopping rules 
This study evaluates the effectiveness and safety of an ERP for chronic subdural hematoma patients. 
Protocol deviation will be noted but does not lead to subject withdrawal. All patients will be invited 
to complete the 6-month questionnaires unless patient deceased.  

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 12 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
6. Statistics and Data Analysis 
 Clearly define the study hypotheses which will be the object of statistical testing, and provide comprehensive 
outcome definitions. If no detailed Statistical Analysis Plan (SAP) will be developed, than provide a detailed description 
of statistical principles (e.g. justification of sample size, confidence levels and p-values, handling of protocol deviations 
and incomplete data, analysis methods, which software will be used, etc.)    
 
The hypothesis of the study is that implementation of an ERP for chronic subdural hematoma patients 
leads to fewer complications, shorter length-of stay and cost-reduction without increasing hematoma 
recurrence rate.  
We hypothesize that we can include about 150 patients in our study over a 3-year study period. With 
a one-sided alpha of 0.05, a non-inferiority margin of 10% and an expected primary endpoint rate 
(recurrence rate) of 11%, we can reach a calculated power of 60%. The final power of the study will 
be higher due to a larger pre-ERP patient cohort (retrospective analysed over a 10-year period) and 
because correction for baseline variables will be performed (cfr. infra). A non-inferiority margin of 
10% seems to be justified, because: 1) the recurrence rate in our hospital is already low according to 
recurrences rates mentioned in literature, 2) an increase of recurrence rate of 10% will be justified if 
effectiveness of the ERP can be proven in terms of complication incidence, mortality and costs, and  
3) with the upcoming usage of adjuvant embolization (= treatment by burr hole evacuation followed 
by prophylactic endovascular embolization in cases with an assumed high risk of recurrence) actual 
recurrence rates are likely to be lower than in the historic patient cohort, in which embolization was 
not routinely performed. 
 
Descriptive statistics will be used to summarize patient baseline characteristics for both patient 
cohorts and baseline imbalance will be analysed. Percentages will be used for categorical variables 
and means and standard deviations or medians and interquartile ranges, when appropriate, for 
continuous variables. The primary endpoint  will be compared between the ERP-cohort and pre-ERP-
cohort using logistic regression for frequency comparison. Secondary endpoints will be analysed using 
appropriate statistics. Categorical data will be compared using Χ² test or Fisher’s exact test. Numerical 
data will be analysed with the student’s t test (for normally distributed continuous variables), Mann-
Whitney U test (for non-normally distributed continuous variables) or the Fisher's exact (for 
categorical data).. Analyses will be adjusted for baseline patient characteristics that are associated 
with the outcome: Markwalder score, hematoma thickness, age and antitrombotic use. Logistic 
regression will be used for adjustments when appropriate. Multiple imputation will be performed is 
there is substantial missing data. Statistica® will be used for statistical analysis. Statistical significance 
will be established at p less than 0.05. All available data will be used. No data imputation will be 
performed. 
7. Data handling  
7.1 General data handling information 
Data collection, handling, processing and transfer for the purpose of this Study will be performed in 
compliance with applicable regulations, guidelines for clinical studies and internal procedures.  It remains 
the responsibility of the Investigator to check that all data relating to the Study, as specified in the Study 
protocol, are entered into the electronic Case Report Form ((e)CRF) in accordance with the instructions 
provided and that the forms are filled out accurately, completely and in a timely manner. 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 13 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
(e)CRFs are provided by the Sponsor for each participant. The Study data will be transcribed from the 
source records into an (e)CRF by Study Staff.  
The (e)CRFs shall under no circumstances capture personal data such as but not limited to the 
participant or their relative(s) name, home address, contact details, full date of birth, medical record 
number (e.g. UZ Leuven EAD number), social security number etc.  
Transfer of the pseudonymized data will be performed via a secured method of transfer taking into 
account all applicable security arrangements and regulations (such as the European General Data 
Protection Regulation). The receiving party will be bound by contractual agreement to keep the 
transferred data confidential at all times and to only process the data for the purpose of the Study. To 
this end, appropriate Data Transfer Agreements (DTAs) will be established.  
7.2   
 Provide details of electronic CRF that will be used, describe the database and specify what kind of data will be 
collected  
 
REDcap will be used to capture study related data. 
The following data will be collected in the (e)CRF : 
- 
Demographic data:  
o 
Age 
o 
Gender 
- 
Baseline data 
o 
NIHSS score 
o 
mRS (modified Rankin Scale) 
o 
Markwalder score 
o 
Antithrombotic agents use and indication. 
o 
History of recent head trauma 
o 
Radiographic characteristics: hematoma side, uni-or bilateral hematoma, hematoma 
thickness, hematoma volume, amount of midlineshift, predominant hematoma density 
(hypodens, isodens, hyperdense or membranous) 
o 
Risk of falling ( > 1 per month) 
o 
Excessive alcohol use 
o 
Cerebral atrophy 
o 
EQ-5D-5L 
- 
Treatment variables 
o 
Type of anesthaesia (general, local, local with sedations) 
o 
Duration of operation 
o 
Uni-or bilateral surgery 
o 
Number of burr holes 
o 
Catheterisation technique (subdural vs subperiostal) 
o 
Drainage system (Jackson-Pratt vs conventional Codman collector system) 
o 
Embolisation technique 
o 
Embolization device 
- 
Timing 
o 
Date of admission 
o 
Date of IC 
o 
Length of stay 
o 
Date of treatment  
o 
Date of discharge 
o 
Date of clinical follow-ups 
o 
Date of end-of-trial (EOT) + cause of EOT 
- 
Costs of hospitalisation 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 14 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
- 
Restart time of antithrombotic agent 
- 
All medical and surgical complications 
- 
Seizures 
- 
Postoperative NIHSS and mRS (assessed at 4-6 w and 6 ± 1 months postintervention) 
- 
Postoperative hematoma volume and thickness 
- 
Readmission + date 
- 
30-day mortality 
- 
EQ-5D-5L at 6-month 
7.3 Direct Data Access 
  Please specify or make reference to another written agreement) that the investigator(s) and the institution(s) will 
permit trial-related monitoring, audits, EC review, and regulatory inspections (where appropriate) by providing direct 
access to source data and other documents (i.e. patients’ case sheets, blood test reports, X-ray reports, histology 
reports etc). 
The Investigator will make source data and documents for this study available to an appropriately qualified 
quality assurance auditor mandated by the CTC, ethical committee and to regulatory authority inspectors, 
after appropriate notification. 
8. Ethical and Regulatory Considerations 
8.1 Ethics Committee (EC) review & reports  
 
Before the start of the Study, this protocol and other related documents will be submitted for review to 
the EC for Study authorization. The Study shall not commence until such approvals have been obtained 
and until other relevant essential Study documents, such as duly signed contract agreements, evidence of 
adequate Study financing etc. are in place. 
8.2 Protocol / GCP compliance 
The Study must be performed in accordance with the protocol, current ICH and ICH-GCP guidelines, and 
applicable regulatory and country-specific requirements. ICH guidelines are an international ethical and 
scientific quality standard for designing, conducting, recording, and reporting studies that involve the 
participation of human participants. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of Study participants are protected, consistent with the principles that originated in 
the most recent version of the Declaration of Helsinki, and that the Study data are credible, reliable and 
reproducible. 
8.3 Data protection and participant confidentiality 
The Study will be conducted in compliance with the requirements of the EU General Data Protection 
Regulation 2016/679 (GDPR), and the relevant Belgian laws implementing the GDPR including the Belgian 
Privacy Act of 30 July 2018 on the protection of privacy in relation to the processing of personal data. 
Any collection, processing and disclosure of personal data, such as participant health and medical 
information is subject to compliance with the aforementioned personal data protection laws (cfr. Data 
Processing Annex (DPA) in Appendix). In case personal data is transferred outside the European 
Economic Area, safeguards will be taken by the Sponsor to ensure that appropriate protection travels 
with the data in accordance with the GDPR. (https://ec.europa.eu/info/law/law-topic/data-
protection/international-dimension-data-protection/rules-international-data-transfers_en#documents) 
Any personal data shall be treated as confidential at all times including during collection, handling and use 
or processing, and the personal data (including in any electronic format) shall be stored securely at all times 
and with all technical and organizational security measures that would be necessary for compliance with 
EU and national data protection legislation (whichever is more stringent). The Sponsor shall take 
appropriate measures to ensure the security of all personal data and guard against unauthorized access 
thereto or disclosure thereof or loss or destruction while in its custody. 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 15 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
9. Research Registration, Dissemination of Results and 
Publication Policy 
The Declaration of Helsinki (latest version) and European and Belgian regulations require that every 
research Study involving human participants be registered in a publicly accessible database before 
recruitment of the first participant. The CI is responsible for registering the Study.  
In addition, the CI will fulfil their ethical obligation to disseminate and make the research results publicly 
available. As such the CI is accountable for the timeliness, completeness and accuracy of the reports. 
Researchers, authors, Sponsors, editors and publishers must adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive, as well as positive results must be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in 
publication.  
 
 The below section can be revised provided that compliance with ethical principles is maintained 
Publications will be coordinated by the CI. Authorship to publications will be determined in accordance 
with the requirements published by the International Committee of Medical Journal Editors and in 
accordance with the requirements of the respective medical journal.  
For multicentre Studies, it is anticipated that the primary results of the overall Study shall be published in 
a multicentre publication. 
Participating Sites are not allowed to publish any subset data or results from the Study prior to such 
multicentre publication.  
Any publication by a Participating Site must be submitted to the Sponsor for review at least thirty (30) 
calendar days prior to submission or disclosure. Sponsor shall have the right to delay the projected 
publication for a period of up to three (3) months from the date of first submission to the Sponsor in order 
to enable the Sponsor to take steps to protect its intellectual property rights and know-how.  
 
10. Insurance/Indemnity 
 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
Sponsor shall assume, even without fault, the responsibility of any damages incurred by a Study Patient 
and linked directly or indirectly to the participation to the Study, and shall provide compensation 
therefore through its insurance. 
11. References 
1. 
Feghali J, Yang W, Huang J. Updates in Chronic Subdural Hematoma: Epidemiology, Etiology, 
Pathogenesis, Treatment, and Outcome. World Neurosurg. 2020;141:339-45. 
2. 
Link TW, Rapoport BI, Paine SM, Kamel H, Knopman J. Middle meningeal artery embolization 
for chronic subdural hematoma: Endovascular technique and radiographic findings. Interv 
Neuroradiol. 2018;24(4):455-62. 
3. 
Foelholm R, Waltimo O. Epidemiology of chronic subdural haematoma. Acta Neurochir 
(Wien). 1975;32(3-4):247-50. 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 16 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
4. 
Duerinck J, Van Der Veken J, Schuind S, Van Calenbergh F, van Loon J, Du Four S, et al. 
Randomized Trial Comparing Burr Hole Craniostomy, Minicraniotomy, and Twist Drill Craniostomy 
for Treatment of Chronic Subdural Hematoma. Neurosurgery. 2022;91(2):304-11. 
5. 
Kudo H, Kuwamura K, Izawa I, Sawa H, Tamaki N. Chronic subdural hematoma in elderly 
people: present status on Awaji Island and epidemiological prospect. Neurol Med Chir (Tokyo). 
1992;32(4):207-9. 
6. 
Balser D, Farooq S, Mehmood T, Reyes M, Samadani U. Actual and projected incidence rates 
for chronic subdural hematomas in United States Veterans Administration and civilian populations. J 
Neurosurg. 2015;123(5):1209-15. 
7. 
Adhiyaman V, Chattopadhyay I, Irshad F, Curran D, Abraham S. Increasing incidence of 
chronic subdural haematoma in the elderly. QJM. 2017;110(6):375-8. 
8. 
Rauhala M, Helén P, Huhtala H, Heikkilä P, Iverson GL, Niskakangas T, et al. Chronic subdural 
hematoma-incidence, complications, and financial impact. Acta Neurochir (Wien). 
2020;162(9):2033-43. 
9. 
Ducruet AF, Grobelny BT, Zacharia BE, Hickman ZL, DeRosa PL, Andersen KN, et al. The 
surgical management of chronic subdural hematoma. Neurosurg Rev. 2012;35(2):155-69; discussion 
69. 
10. 
Stanišic M, Pripp AH. A Reliable Grading System for Prediction of Chronic Subdural 
Hematoma Recurrence Requiring Reoperation After Initial Burr-Hole Surgery. Neurosurgery. 
2017;81(5):752-60. 
11. 
Liu HY, Yang LL, Dai XY, Li ZP. Local anesthesia with sedation and general anesthesia for the 
treatment of chronic subdural hematoma: a systematic review and meta-analysis. Eur Rev Med 
Pharmacol Sci. 2022;26(5):1625-31. 
12. 
Shapey J, Glancz LJ, Brennan PM. Chronic Subdural Haematoma in the Elderly: Is It Time for a 
New Paradigm in Management? Curr Geriatr Rep. 2016;5:71-7. 
13. 
Markwalder T-M, 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. 
 
 
 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 17 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
 
12. Supplemental Content 
Summery overview of pre-ERP and ERP care elements 
 
Pre-ERP 
ERP 
Treatment modality 
 
 
Surgical treatment modality 
Mostly burr hole drainage 
Preferably burr hole drainage, 
craniotomy only when deemed 
necessary according to treating 
neurosurgeon based on clinical 
or radiographic factors. 
Adjuvant embolization of the 
middle meningeal artery 
Not routinely performed 
In cases with assumed high risk 
of reccurence (use of 
anticoagulants, severe brain 
atrophy, high fall risk, ethanol 
abuse …) adjuvant 
(prophylactic) emobilization can 
be performed. 
Anaesthesia 
 
 
Anaesthesia 
Mostly combination of 
general and local anaesthesia  
Local anaesthesia with sedation 
when possible. 
Surgical technique 
 
 
Number of burr holes 
2 
1 
Irrigation 
Irrigation performed 
Irrigation with fluid at body 
temperature performed 
Catheterisation technique 
Subdural drainage 
Subgaleal drainage 
Catheterisation material 
Codman® External Drainage 
System 
A Jackson-Pratt drainage 
system 
Postoperative management 
 
 
Mobilisation 
48h bedrest 
Immediate mobilisation with 
physiotherapist or nurse. 

UZ/KU Leuven 
 
 
Protocol: ERP-cSDH 
Internal Ref.: S68819 
 
 
Version: 2_14July2024 
 
CTC GEN-TMP-003-1.0_28Jul2020  
Page 18 of 18                                        Protocol template for 
observational                                                                                                    
                                                                                    Confidential & Proprietary                                                clinical research study  
Duration of drainage 
48h 
At least 24u 
Postoperative imaging 
At 2 days postoperative 
Only at indication 
Discharge 
At discretion of neurosurgeon 
At discretion of neurosurgeon 
Restart of 
anticoagulants/antithrombotic 
At discretion of neurosurgeon 
At discretion of neurosurgeon 
Follow-up 
Clinical follow-up at 4-6 weeks 
postoperative, with CT-scan 
Clinical follow-up at 4-6 weeks 
postoperative, with CT-scan, 
and clinical follow-up at 6 
months