Title: A randomised, double blind, placebo-controlled trial of a two-week course of dexamethasone for adult patients with a symptomatic Chronic Subdural Haematoma (Dex-CSDH trial)
Funder: Department of Health and Social Care

Abstract: • PRINCIPAL RESEARCH QUESTION: In adult patients with a symptomatic chronic subdural haematoma (CSDH), what is the clinical and cost-effectiveness of a two-week course of dexamethasone compared to placebo? • DESIGN: The Dex-CSDH study is a randomised, double blind, placebo-controlled trial of a two-week course of dexamethasone for adult patients with a symptomatic CSDH. Following successful completion of the internal pilot phase, we intend to roll out the substantive trial across the NHS. 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 CSDH management and research, academics in the field of ageing research, members of the Cambridge Clinical Trials Unit, health economists and service user representatives. The project is supported by the Academic Committee of the Society of British Neurological Surgeons and the UK Neurosurgical Research Network. • SETTING: Participant enrolment, allocation and treatment will take place in participating neurosurgical units (NSU). • TARGET POPULATION: The study focuses on adult patients with a symptomatic CSDH confirmed on cranial imaging. CSDH is defined as a predominantly isodense or hypodense collection in the subdural space along the cerebral convexity on CT scanning. Symptoms that may be attributed to a CSDH include headache, gait disturbance, falls, confusion/cognitive disturbance, focal neurological deficit, speech disturbance, drowsiness/decreased consciousness and seizures. As per routine practice, the responsible clinical team will judge whether or not a symptom is attributable to the CSDH. - Inclusion criteria: 1. Adult patients aged 18 years or older. 2. Symptomatic CSDH confirmed on cranial imaging (e.g. CT/MRI - predominantly hypodense or isodense crescentic collection along the cerebral convexity on CT). 3. Patient or Legal Representative is willing and able to provide informed consent or in the absence of a legal representative, an Independent Healthcare Professional provides authorisation for patient enrolment. - Exclusion criteria: 1. Patients with conditions where steroids are clearly contra-indicated. 2. Patients who are on (or within 1 month of) regular oral or intravenous glucocorticoid steroids*. 3. Previous enrolment in this trial for a prior episode 4. Time interval from the time of admission to NSU to first dose of trial medication exceeds 72 hours. 5. CSDH in the presence of a cerebrospinal fluid (CSF) shunt. 6. Severe lactose intolerance or any known hypersensitivity to dexamethasone or any of the IMP (investigational medicinal product) excipients. 7. Patients with a previous history of psychotic disorders. 8. Unwillingness to take products containing gelatin. 9. Concurrent enrolment in any other trial of an investigational medicinal product. *Patients on topical or inhaled steroids are allowed to be recruited into the trial, as are patients who have had 1 intra-operative dose of dexamethasone for anti-emesis. • HEALTH TECHNOLOGIES BEING ASSESSED: A CSDH is a collection of liquefied blood between the dura mater (the outer lining of the brain) and the brain. In symptomatic patients with a CSDH exerting pressure on the brain the role of surgical evacuation of the liquefied blood is well established. The risk of symptomatic recurrence following evacuation is about 15-20% and this may require repeat surgical intervention if symptomatic. This has been shown to adversely affect long-term functional outcome. There is evidence from our previous trial of CSDH that the use of an intervention to reduce recurrence (subdural drain) also resulted in reduction in mortality and rate of poor outcome at 6 months. A considerable body of evidence suggests that administration of steroids can reduce the recurrence rate and the rate of surgical interventions. However, there is no high-quality evidence showing that steroids can improve functional outcome. The Dex-CSDH study aims to assess the clinical- and cost-effectiveness of a two-week course of dexamethasone (intervention) compared to placebo (control). A 2-week course of dexamethasone provides the best balance in terms of clinical efficacy (median time to recurrence after surgical evacuation is 12 days) and risks (risk of adverse events increases with longer duration of administration). • ENROLMENT AND CONSENT: Patients with a CSDH usually present to their local Emergency Department. Following cranial imaging, symptomatic patients are referred and admitted to a NSU for further management. Upon admission to the NSU, patients are assessed by the on-call neurosurgical team. These processes are part of the standard care pathway for patients with a CSDH in the UK. Screening of patients to determine eligibility for participation in the trial will be undertaken by the on-call neurosurgical team. Informed consent for participation in the study will be obtained from the patient or the patient’s representative agreement will be sought if the patient lacks capacity. If the patient’s representative cannot be contacted in the allowed time frame, then the agreement of an independent (not directly involved with the study) clinician will be necessary. • TREATMENT ALLOCATION & INTERVENTION: Participants will be randomly assigned to either control or intervention group with a 1:1 allocation as per a computer generated randomisation schedule stratified by site using permuted blocks of random sizes. Drug packs will be labelled with a unique and randomly generated identification number to ensure blinding during routine practice and allow emergency unblinding if required. Following randomisation, patients will receive a two-week course of either dexamethasone or placebo. The rest of the treatment pathway is unchanged from the usual NHS pathway, with further management (including decision for surgical intervention and the timing of such intervention) to be decided by the responsible clinical team, who will remain blinded to the allocation. Irrespective of whether or not an operation is undertaken, patients will complete the two-week course of trial medication • MEASUREMENT OF COSTS AND OUTCOMES: The primary outcome measure will be the modified Rankin Scale (mRS) at 6 months post-randomisation as it is a core instrument for measuring the degree of disability or dependence in the daily activities. Follow-up at 6 months will be undertaken by blinded assessors when patients return for their follow-up appointment. Patients unable to attend the outpatient clinic will be followed up with postal questionnaires. The study will also include the following secondary outcome measures: - Rate of CSDH-related surgical interventions undertaken during the index admission - Rate of CSDH-related surgical interventions undertaken during subsequent admissions - Level of consciousness (Glasgow Coma Scale) at discharge from NSU and 6 months - mRS score at discharge from NSU and 3 months - Barthel Index at discharge from NSU, 3 months and 6 months - EuroQOL (EQ-5D) at discharge from NSU, 3 months and 6 months - Serious adverse events and complications An economic analysis will be conducted alongside the trial. Costs will be estimated from the viewpoint of the NHS and personal social services (PSS). Resources associated with the provision of dexamethasone will thereby be monitored along with e.g. length of stay (in the NSU and the total for the original hospital stay) and any hospital re-admissions. A cost-utility analysis will be conducted, where quality of life will be measured using the EQ-5D to generate Quality Adjusted Life Years. • SAMPLE SIZE: An absolute 8% increase in the rate of favourable outcome (mRS 0-3) at 6 months is a plausible and clinically important treatment effect. Assuming a favourable outcome rate of 80-85% in the control group and using a 2-sided test at the 5% significance level, a sample size of 750 patients (allowing for a 15% loss to follow-up) will enable us to detect an 8% absolute difference in the rate of favourable outcome with a power of 81-92%. • PROJECT TIMETABLE: - Months 1 to 5 (March 2015-July 2015): trial set-up - Months 6 to 14 (Aug 2015 - April 2016) : internal pilot study (100 patients in 7 SITES) - Months 15 to 48 (May 2016 - Feb 2019) substantive trial (650 patients in 22 SITES) - Months 49 to 54: completion of follow-up - Months 54 to 59: trial close down and analysis The recruitment rate has been estimated at 2 patients per site per month. On the basis of hospital episode statistics (HES) and data from the national CSDH audit, approximately 60-80 patients with a CSDH are admitted in a medium-sized neurosurgical unit each year. Hence, the estimated recruitment rate is feasible. In addition, 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.

Lay abstract: Chronic subdural haematoma (CSDH) is a collection of liquefied blood between the surface of the brain and its outmost lining. It is especially common in older individuals and can happen with only a minor injury to the head. It can cause drowsiness, confusion, limb weakness and problems with mobility. In the UK, 5,000 people aged over 65 years are diagnosed with a CSDH each year. In the NHS, patients with severe symptoms usually undergo an operation to evacuate the CSDH. Patients with milder symptoms are usually actively monitored. Although about 80-85% of the patients tend to recover well from this operation, approximately 15-20% of patients will have a recurrence of the CSDH and require a further operation. This significantly reduces the chances of good recovery. A considerable body of evidence suggests that steroids can reduce the rate of recurrence and, in some cases, avoid the need for surgery altogether. However, steroids have side effects and it is not known whether the benefits outweigh the risks in this context. Currently, there is no high-quality evidence showing whether steroids should be used routinely for patients with CSDH. The Dex-CSDH study will provide this much needed evidence. The Dex-CSDH study will focus on symptomatic patients with CSDH and will compare the use of steroids against placebo ('dummy' treatment). The study was designed as a collaborative effort involving members of the British Neurosurgical Trainee Research Collaborative (www.bntrc.org.uk), clinicians experienced in CSDH management and research, academics in the field of ageing research, members of the Cambridge Clinical Trials Unit, health economists and service user representatives. The project is supported by the Academic Committee of the Society of British Neurological Surgeons and the UK Neurosurgical Research Network. Symptomatic patients with a CSDH are referred and admitted to a neurosurgical unit (NSU) for further care. This process is part of standard NHS care. All patients admitted to a participating NSU with CSDH will be considered for the study based on pre-specified criteria. When patients are too unwell to consent, the agreement of a representative will be sought. If such a representative is not contactable, the agreement of an independent doctor will be sought. Following consent, patients will be randomly placed into two groups. One group of patients will receive steroids for 2 weeks, and the other a placebo. All patients will otherwise be managed as per usual NHS clinical practice. The decision for surgery or active monitoring will be made on an individual patient basis by the clinical team in conjunction with the patient and their families. The study will start with a pilot phase (100 patients) in order to ensure that enrolment and follow-up run smoothly. If the pilot is successful, we will roll out the substantive study across the NHS (an additional 650 patients). All participants will be followed up for 6 months to see how well they recover, and whether they had a recurrence of their CSDH and required surgery. The main outcome measures focus on activities of daily living and performance, cognitive status and quality of life. We will also undertake an economic analysis. An independent committee will be responsible for monitoring the safety, rights and well-being of study participants.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS;NEUROLOGICAL