Title: Randomised Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute Subdural Haematoma (RESCUE-ASDH)
Funder: Department of Health and Social Care

Abstract: • DESIGN RESCUE-ASDH is a multi-centre, pragmatic, parallel group randomised trial that aims to compare the clinical and cost-effectiveness of decompressive craniectomy versus craniotomy for the management of adult head-injured patients undergoing evacuation of an acute subdural haematoma (ASDH). It will commence with an internal pilot which, if successful, will be followed by the main trial. The project was designed as a collaborative effort involving members of the British Neurosurgical Trainee Research Collaborative (BNTRC; www.bntrc.org.uk), clinicians experienced in head injury management, academics experienced in head injury research, members of the Cambridge Clinical Trials Unit, health economists and service user representatives. In addition, there is there is increasing evidence that trainee involvement in trials is feasible and can lead to more efficient recruitment (e.g. NIHR RfPB-funded ROSSINI trial). Therefore, neurosurgical trainee members of the BNTRC will play a central role in the delivery of the trial. • HEALTH TECHNOLOGIES BEING ASSESSED Approximately two-thirds of head-injured patients undergoing emergency brain surgery have an ASDH evacuated. When an ASDH is evacuated, the bone flap can be left out or replaced prior to closing the skin. The RESCUE-ASDH trial will compare these two specific components of the operation to remove an acute subdural haematoma (i.e. bone flap left out prior to closing the skin versus bone flap replaced prior to closing the skin). Both options are widely practised and accepted but they have never been compared head-to-head in a randomised trial. When the bone flap is replaced prior to closing the skin, the operation is named craniotomy. On the other hand, when the bone flap is left out, the operation is named decompressive craniectomy (DC). The advantage of a DC is that it is effective in controlling brain swelling which is often a problem in the days after the operation. When the swelling goes down, the patient has another operation to reconstruct the skull (cranioplasty). The advantage of a craniotomy is that the patient will not need a later operation to rebuild the skull. However, it may fail to control brain swelling in some patients. • TARGET POPULATION The study is focusing on adult head injured patients who require an operation to evacuate an ASDH. Inclusion criteria: - Adult head-injured patients (>16 years) - Acute subdural haematoma on CT* - The admitting neurosurgeon feels that the haematoma needs to be evacuated with a large bone flap (recommended size =11 cm anteroposterior diameter) either by a craniotomy or decompressive craniectomy* *Patients with additional lesions (e.g. intracerebral haemorrhage, contusions) can be included Exclusion criteria: - Bilateral acute subdural haematomas both requiring evacuation - Previous enrolment in RESCUE-ASDH study - Severe pre-existing physical or mental disability or severe co-morbidity which would lead to a poor outcome even if the patient made a full recovery from the head injury • SETTING Patient enrolment (including screening for eligibility and consent) will occur in hospitals with neurosurgical services in the UK and other countries around the world. • MEASUREMENT OF OUTCOMES The primary endpoint will be the extended Glasgow Outcome Scale (GOSE) at 12 months post-injury. The use of the GOSE as a core global outcome measure is recommended by the interagency Traumatic Brain Injury (TBI) Outcomes Workgroup and the International Mission for Prognosis and Analysis of Clinical Trials in TBI group (IMPACT). The secondary endpoints are: - GOSE at 6 months post-injury - Quality of life (EQ-5D) at discharge from neurosurgical unit (NSU), 6 and 12 months post-injury - Glasgow Coma Scale (GCS) on discharge from the intensive care unit (ICU) and from NSU - Length of stay in ICU, neurosurgical and rehabilitation unit - Therapy Intensity Level (IMPACT scale) in the ICU - Discharge destination from NSU - Mortality - Serious adverse events & surgical complications during index admission - Cranial surgery within 2 weeks after randomisation - Subsequent readmissions to the NSU within the 12 months follow-up period - Hydrocephalus requiring shunt insertion within the 12 months follow-up period - Health care services utilisation over 12 months - Detailed economic evaluation • SAMPLE SIZE Retrospective studies suggest a favourable outcome in about 35% of patients undergoing evacuation of ASDH. At the outset of the trial in 2014, the group of co-applicants deemed an 8% treatment effect as a clinically important difference. Subsequently, a formal sample size calculation was performed with the nQuery Advisor Version 7.0, using a Wilcoxon-Mann-Whitney rank-sum test for ordered categories. We estimated that a sample of 990 patients would allow us to detect the equivalent of an absolute difference of 8% in the proportion of participants at 12 months after randomisation with a favourable outcome [90% power and 2-sided significance 0.05 (35% vs 43%) 10% drop out rate] with ordinal analysis. Mortality is recorded as part of the GOSE (death – GOSE score 1), so it will not impact on loss to follow-up. In addition, a simulation study was undertaken to look at the impact on statistical power of covariate (age, GCS motor score and pupillary reaction) adjustment over and above the ordinal analysis. The simulation study confirmed that the planned sample size of 990 patients, would give over 90% power to detect an 8% treatment effect. Therefore, we intend to use the proportional odds model adjusted for covariates in the analysis of the trial. However, it was clear by 2017, that the sample of 990 at outset of the trial might not be appropriate given discussions in the neurosurgical community that evidence of a larger treatment effect is required to encourage surgeons to change their practice, especially when the intervention in question (i.e. craniectomy) will necessarily lead to a second operation (i.e. cranial reconstruction). A survey amongst an international pool of neurosurgeons who have expertise in neurotrauma and are interested in the study question was undertaken. The results showed that the mean NNT that would lead these surgeons to change their practice was 7. We believe that surgeons who do not have expertise or interest in neurotrauma are likely to suggest that an even lower NNT would be necessary in order to lead to a practice change. A NNT of 7 is equivalent to a 14% treatment effect and the sample size was re-estimated (using WinPepi version 11.65) in 2018 using this treatment effect giving a sample size of 440, allowing for a 10% drop out rate. The new sample size of 440 will have more than 80% power for a 14% treatment effect with binary analysis (corresponding to NNT of 7); more than 80% power for a 12% treatment effect with ordinal analysis and more than 90% power for a 14% treatment effect with ordinal analysis. The results of the survey and the implication for sample size adjustment were discussed at the HTA and TSC meetings, both unanimously agreed that reducing the sample size to 440 randomised patients was valid, based on these results. If the target sample size of 440 is reached before 30 April 2019 (end of study recruitment date), we will continue recruiting patients until the end of the recruitment period. • PROJECT TIMETABLE (Concise summary) - Months 1 to 3: regulatory approvals - Months 4 to 21: internal pilot phase - Months 22 to 58: substantive trial - Months 59 to 70: follow-up - Months 71 to 77: analysis

Lay abstract: It is estimated that 4,000 head-injured patients have emergency brain surgery each year in the UK. Two-thirds of head-injured patients requiring emergency surgery have a blood clot between the outer lining of the brain and the brain itself. This is called an acute subdural haematoma (ASDH). The pressure this clot puts on the brain can be life threatening, so an urgent operation is needed to remove it. When an ASDH is surgically evacuated, a piece of skull can be left out or replaced prior to closing the skin. When a piece of skull is replaced prior to closing the skin, the operation is named craniotomy. On the other hand, when a piece of skull is left out, the operation is named decompressive craniectomy (DC). The steps of a craniotomy are: opening of the skin, removal of a piece of skull, removal of the clot, replacement of the piece of skull, closure of the skin. The steps of a DC are: opening of the skin, removal of a piece of skull, removal of the clot, closure of the skin (i.e. the piece of skull is not replaced prior to closing the skin). The advantage of a DC is that it is more effective in controlling brain swelling which is often a problem in the days after the operation. After a few months, the patient has another operation to rebuild the skull (with the patient's own bone or an artificial material). The advantage of a craniotomy is that the patient will not need a later operation to rebuild the skull. However, craniotomy may fail to control the brain swelling in some patients. All neurosurgeons are capable of performing both types of operation. Currently, there is no high-quality evidence showing if one operation is better than the other. We intend to undertake a study to provide this much needed evidence. The study design is described below: • How: Following consent, patients will be put into two groups at random. One group of patients will receive the craniotomy, while the other group will have the DC. This study design allows us to perform a head-to-head comparison of the two options and is the only way to find out if one is better than the other. This type of study is called a randomised trial. Patients unsuitable for inclusion in the study (e.g. when significant brain swelling prevents safe replacement of the piece of skull) will have the operation deemed to be in their best interests by the operating neurosurgeon. All participants will be followed up for 1 year to see how well they recover. We aim to recruit 440 patients in the randomised trial. If the target sample size of 440 is reached before 30 April 2019 (end of study recruitment date), we will continue recruiting patients until the end of the recruitment period. • Where: The study will take place in hospitals with neurosurgical services. • Outcomes: The main outcome measure (extended Glasgow Outcome Scale) will reveal the impact of the head injury on the level of consciousness, functional independence, work and quality of life. Participants will be followed-up for 1 year after their injury. All participants will be carefully monitored for complications. In addition, a detailed economic evaluation will be undertaken by the health economists of the study team. • Ethical issues: Patients will not be able to consent for participation due to the effects of the head injury. In addition, this study is occurring in the emergency setting, where a significant delay in starting the operation could have detrimental effects to the patient. Often the next of kin cannot be traced or is not available on site. If the next of kin is available, a discussion about the trial will be had before the operation as long as the treating surgeon believes that this would not delay the operation. In cases where the next of kin cannot be traced or there is no time to discuss trial participation with them prior to providing the treatment, the treating surgeon will take responsibility for entering the patient into the trial provided that certain conditions are met and documented in the treating surgeon declaration form. Furthermore, participants regaining capacity will also be informed about the clinical trial and consent to continue will be sought. An independent committee will be responsible for monitoring the safety, rights and well-being of study participants. • Team: The team of co-applicants comprises of doctors experienced in head injury management and research, a medical statistician, experts in coordinating clinical trials, health economists and a member of the public.

Research activity codes: 6.4 SURGERY
Health categories: INJURIES AND ACCIDENTS