Statistical analysis plan for the Dex-CSDH trial: a randomised, double-blind, placebo-controlled trial of a 2-week course of dexamethasone for adult patients with a symptomatic chronic subdural haematoma

Chronic subdural haematoma (CSDH) is a collection of blood overlying the surface of the brain which is diagnosed on cranial imaging as a predominantly hypodense or isodense collection in the subdural space on computed tomography [1]. It is especially common in older patients and can happen with only a minor injury to the head or even in the absence of trauma. Symptoms that can be attributed to a CSDH include headache, gait disturbance, falls, confusion, focal neurological deficit, speech disturbance, drowsiness, and seizures.

The incidence of CSDH is increasing [2]. In the UK, approximately 5000 people aged over 65 years are diagnosed with a CSDH each year. In the National Health Service (NHS), patients who are symptomatic usually have an operation to evacuate the CSDH. Patients with very mild symptoms or small collections are usually actively monitored. Although about 80% of patients tend to recover well from surgery, up to 20% of patients will have a recurrence of the CSDH requiring further surgery. This significantly reduces the chances of a good recovery.

One theory on the formation of a CSDH is that, following a traumatic injury, an inflammatory reaction is initiated which drives the growth of abnormal blood vessels and fluid accumulation over the brain surface, supported by findings of high levels of inflammatory markers within the CSDH fluid [3‐6]. Steroids, such as dexamethasone, are thought to help dampen this inflammatory reaction, allowing better resolution of the CSDH and lower likelihood of recurrence. The Dex-CSDH (DEXamethasone in Chronic SubDural Haematoma) trial will determine whether steroids should be prescribed routinely for patients with a symptomatic CSDH.

Dex-CSDH is a multi-centre, clinical phase III, randomised, double-blind, placebo-controlled trial of dexamethasone for up to 2 weeks on clinical outcome following CSDH. In total, 750 symptomatic patients with a radiological diagnosis of CSDH, recruited from neurosurgical units (NSUs) based within the UK, were randomised to a 2-week tapering course of either dexamethasone or placebo stratified by site. The primary outcome measure was the modified Rankin Scale (mRS) at 6 months (dichotomised to 0–3 and 4–6, as used in previous studies [7, 8]), which was adapted from a validated questionnaire [9]. The decision to dichotomise the mRS was based on the clinical interpretability of the outcome and its potential value in future meta-analyses. Secondary outcome measures sought a difference in the acute clinical course, mortality, length of stay in hospital, discharge destination, and adverse events and complications. All research staff and outcome assessors were blinded. Full details of the study design can be found in the protocol [10].

A sample size re-estimation was performed, using data on 450 patients, due to uncertainty in the absolute favourable outcome rate of the primary outcome (score of 0–3) in the control arm. The possible adaptations were to either increase the sample size (up to a maximum of 1000) or to stop the trial for futility if the revised sample size was >1000; the original sample size would be retained if the re-estimated sample size was <750. An Independent Data Monitoring and Ethics Committee (IDMEC) reviewed the sample size re-estimation and recommended the trial continue to recruit to the original target of 750 patients. The investigators remained blinded to the analysis.

The statistical analysis plan (SAP) was written prior to final analysis and unblinding in order to avoid reporting bias and data-driven results. The final outcomes will be collected by July 2019, with the unblinded analysis expected to take place in early 2020. The following sections outline the main analyses featured in the SAP. Full details are provided in Additional file 1.