Explanation for the choice of comparators

Patients assigned to the control group will be managed according to the current standard of care, i.e., neurosurgical evacuation of cSDH by burr hole trepanation and/or any surgical technique without specific added treatment.

Intervention description

Patients assigned to the experimental arm will undergo neurosurgical evacuation of cSDH by burr hole trepanation and/or any surgical technique plus endovascular embolization of the MMA (see Fig. 2).

Fig. 2

Lateral angiograms of the MMA before embolization (A) and after injection of 0.5 ml PVA particles (100–300μm) obstructing the peripheral branches of the MMA (B)

The embolization procedure can briefly be described as follows: A micro-catheter is inserted via a transfemoral approach into the branches of the MMA in a minimally invasive manner, and the periphery is occluded using PVA particles to prevent future bleeding. For this purpose, the micro-catheter is positioned as distally as possible, which prevents dislocation of particles into nutritive branches [29, 35]. If the desired catheter position cannot be achieved due to anatomical conditions, the MMA can optionally be closed more proximally using Onyx® or micro-electric coils. Embolization of the MMA by PVA particles with sizes between 40 and 300 μm is preferred over embolization by coils and Onyx®, since the capillary network of the dura is entirely blocked when using particles [35]. After using coils, a faster reperfusion via collaterals might be possible.

Target vessels are identified by digital subtraction angiography (DSA) in patients assigned to the intervention group, meaning increased exposure to radiation. Based on embolization of MMA branches in meningioma patients, a dose area product (DAP) of about 6000 to 16,000 centi-gray centimeter squared (cGy per cm2) is expected depending on the extent of embolization and individual anatomy. Thus, it is very much unlikely the DAP associated with the experimental adjunct exceeds the reference value for neuroradiological interventions of 20,000 to 30,000 cGy per cm2 as defined by the Federal Office for Radiation Protection of Germany (“Bundesamt für Strahlenschutz”, BfS). The trial and imaging protocol was approved by the BfS on March 25, 2022, under notification reference ZD 3-22464/2022-015-A.

Criteria for discontinuing or modifying allocated interventions

Patients may withdraw their consent at any time without providing a reason and thus terminate their participation in the study prematurely. Withdrawal from the study and reasons, if known, will be documented. Criteria for premature drop-out include:

Moreover, the principal investigator is entitled to terminate the study prematurely if:

Patient recruitment remains inadequate despite multiple measures to improve enrolment

Serious problems with the quality of collected data cannot be resolved

Unforeseeable circumstances at the trial center prevent trial continuation

Unacceptable risks arise (after a risk-benefit assessment by the Data Safety Monitoring Board)

New scientific findings in favor of one or the treatment violate the equipoise principle

Strategies to improve adherence to interventions

There is no possibility to influence patients’ adherence to the intervention. Embolization of the MMA constitutes the only study intervention, which is solely performed by the clinical investigators.

Relevant concomitant care permitted or prohibited during the trial

Except for the study intervention, patients in both groups are treated according to the currently established standard of care at the trial center (ukb). Any concomitant care as part of routine clinical practice is permitted.

Provisions for post-trial care

A proband cover for all patients participating in the study is contracted to compensate for trial-associated harm occurring within 5 years of trial participants’ final study visit.

Outcomes Primary outcome

The primary outcome is cSDH recurrence up to 3 months after surgery. Recurrence is defined by one and/or both of the following criteria:

Recurrence of cSDH is operationalized as a binary outcome (i.e., recurrence or no recurrence) during a follow-up period of 3 months.

Secondary outcomes

The following secondary outcomes will be assessed up to 3 months after surgery:

Neurological deficits evaluated by the modified Rankin scale (mRS)

Quantity and characteristics of recurrence-associated complications

Quantity and characteristics of complications associated with endovascular embolization

The mRS [36] measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. Scale values and interpretations are:

0 = No symptoms.

1 = No significant disability. Able to carry out all usual activities, despite some symptoms.

2 = Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.

3 = Moderate disability. Requires some help, but able to walk unassisted.

4 = Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.

5 = Severe disability. Requires constant nursing care and attention, bedridden, incontinent.

6 = Dead

Tertiary outcomes

The following tertiary outcomes are only addressed in a sub-sample of participants consenting to genetic analyses:

Relationship between factor XIII deficiency (i.e., activity after cryopreservation <70%) and risk of cSDH recurrence

Predisposition of genetic variants F13A1 rs2815822 and F13B rs12134960 for factor XIII deficiency

Participant timeline

Participants in the intervention and control groups will undergo five and four scheduled follow-up visits, respectively (Table 1):

−t1 Screening and informed consent

t0 Randomization

t1 Baseline

t2 Embolization (intervention group only, within 72 h after surgery)

t3 Follow-up 1 month after baseline (± 1 week)

t4 Follow-up 3 months after baseline (± 1 week)

Table 1 Schedule of enrollment, interventions, and assessmentsSample size

Because of the potential of notable morbidity, recurrent cSDH is considered both a clinically relevant and methodologically reliable, objective primary trial endpoint.

In one of the largest studies to date, Ban et al. compared a prospective series of 72 patients with cSDH undergoing MMA embolization with a historic standard-of-care group of 469 subjects. The overall risk difference (irrespective of hematoma evacuation) was estimated at 26% (95% CI 21 to 31%) in favor of endovascular management. There is much variability in reported cSDH recurrence risks with either treatment option, and unclarity about the realistic benefit of combined surgical and interventional therapy.

In view of the results of published studies (in particular Ban et al.), we conservatively presume recurrence rates of 30% in the control and 10% in the experimental arm during an observation period of 3 months.

Since our assumptions are subject to uncertainty, we will employ an adaptive design according to O’Brien-Fleming with one planned interim analysis to decide about the further trial progress, and to modify the target sample size if necessary and/or reasonable. For a power of 80% and a total alpha of 5%, data from 138 patients (i.e., 69 per group) are needed to detect a risk difference of 20% by a z-test for independent samples. Assuming a drop-out and lost-to-follow-up rate of 10%, we plan to enroll 154 patients (i.e., 77 per treatment arm) unless the interim look prompts any adjustment.

Recruitment

During a kick-off meeting, clinical investigators and trial supporting personnel will be trained in communicating with potential study participants and their relatives, documentation including screening logs, and other standard operating procedures established for trial purposes.

In agreement with the funding body, recruitment efficiency will be evaluated 9, 15, and 21 months after randomization of the first patient, using the observed to expected ratio and curve.

In case of insufficient enrollment (i.e., <25% of the number of patients included at a certain time point), investigators will take extra measures to improve recruitment (e.g., increasing awareness among all clinicians, nurses, therapists, expansion of the recruiting team, modification of eligibility criteria, etc.). While it is currently not intended to roll out this trial to other centers, we will negotiate with the funding body to include other institutions if trial aims cannot be achieved otherwise.