Patient and public involvement

There is no direct patient involvement in the design, recruitment or conduct of the study. When the study is completed, the result of this trial will be notified to participants through direct consultation with their trial clinician.

Design

SPSAH trial is a prospective, multicentre, randomised, single-blind, placebo-controlled trial. Figure 1 illustrated the flow chart of the SPSAH trial. This trial will be conducted at four neurosurgical centres, including departments of neurosurgery in West China Hospital, Sichuan University; The Second Affiliated Hospital, Zhejiang University School of Medicine; The First Affiliated Hospital, Harbin Medical University; and People’s Hospital of Leshan. All participating institutions can perform skilled surgical treatment for neurovascular diseases, including clipping and endovascular therapy for ruptured aneurysms. The study starts recruitment in August 2021 and is anticipated to complete in December 2022.

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Figure 1

SPSAH trial flow chart. aSAH, aneurysmal subarachnoid haemorrhage; CTA, CT angiography; DSA, digital subtraction angiography; MoCA, Montreal Cognitive Assessment; mRS, modified Rankin Scale; SPSAH, seizure prophylaxis following aneurysmal subarachnoid haemorrhage.

Patient population: inclusion and exclusion criteria

Patients will be considered eligible if they meet all of the following inclusion criteria:

• Age ≥18 years old.

• mRS score 0–1 before ictus.

• CTA or DSA confirmed diagnosis of aSAH caused by rupture of anterior circulation aneurysm.

• Symptoms onset of aSAH occurred <24 hours prior to presentation at the hospital.

• Hunt-Hess grade ≤3 on admission.

• Surgical clipping is planned for treatment.

• Patient is willing and able to accept long-term study follow-up.

• Patient or their legally authorised representative (LAR) has provided written informed consent.

The following patients will be excluded:

• Concurrent non-ruptured aneurysm on the same admission.

• SAH secondary to rupture of traumatic or infected aneurysm.

• Prior anticonvulsant therapy or epilepsy.

• Seizure before enrolment.

• Use of carbapenem antibiotics within 7 days before enrolment.

• History of coagulopathy.

• Concurrent significant intracranial pathology, including but not limited to Moyamoya disease, arteriovenous malformation, arteriovenous fistula or malignant brain tumour.

• Serious comorbidities, including but not limited to dementia, severe major depression, cancer (likely to cause death in 2 years), multisystem organ failure.

• History of previous ruptured cerebral aneurysm.

• Liver dysfunction (clinical laboratory markers for liver function three times greater than normal or cirrhosis), with acute or chronic hepatitis, history or family history of serious hepatitis (especially drug-induced hepatitis).

• Known allergy to sodium valproate.

• Pregnant woman.

• Patients and/or LAR refuse treatment.

• Enrolment in another research study that would conflict with this study.

• Any other reason that the investigator considers the patient is inappropriate for enrolment.

Randomisation

The central random method will be adopted in this research, and West China Hospital will undertake the central randomisation. All eligible patients will be randomly allocated to either intervention or placebo using a computer-generated random number. We apply the evaluator-blinded design. Clinicians in charge of patients’ treatment will know the allocation of patients. The follow-up evaluator will not know each patient’s grouping. After the final statistical analyses have been finished, the randomisation sequence will be non-blinded.

Intervention

All participants will be delivered standard treatment according to the latest guidelines and expert consensus.18 19 The standard treatment mainly includes blood pressure control, euvolaemia maintenance, nimodipine, neurological monitoring, deep venous thrombosis prophylaxis and general care. Patients allocated into the intervention group will receive sodium valproate 20 mg/kg daily intravenously in 0.9% normal saline (divided to two times per day, once every 12 hours). Patients allocated into the control group will receive matching placebo. Sodium valproate will be supplied by the local hospital.

Primary outcomes

The incidence of total seizures is the primary outcome of this study. We only record clinical seizures, while subclinical seizures will not be recorded. Diagnosis of seizure is mainly based on the description from medical staff, patients themselves or the caregiver.

Secondary outcomes

The secondary outcome includes the incidence of early seizures (≤7 days from SAH ictus), the incidence of late seizures (≥7 days from ictus), aSAH-related complications (mainly include rebleeding, fever, pulmonary and urinary infection, cerebral vasospasm, cerebral infarction), sodium valproate-related adverse effects, mRS (on discharge, at 90 days, 180 days), rate of good outcomes (mRS 0–2 will be defined as ‘good outcome’), all-cause death (at 90 days, 180 days) and MoCA score (at 180 days). The mRS will be assessed by a neurologist using structured interviews.26 All neuropsychiatric evaluations (MoCA, Chinese version) will be performed by a qualified specialist in psychiatry.

Data monitoring body

This study will be conducted according to the principles of Declaration of Helsinki and good clinical practice guidelines. An independent data safety and monitoring board (DSMB) composed of physicians, neurosurgeons and intensivists will independently perform non-blinded reviews of all patients’ efficacy and safety data, including adverse events (AEs) and dropout rates, reported from informed consent to 180 days postrandomisation. The DSMB will meet at least every 6 months and hold an interim analysis meeting when half cases have finished 180 days of follow-up. The data generated in our study will be handled while parametricmaintaining the anonymity and confidentiality of the participants.

Any untoward medical occurrence of the enrolled patients during this trial will be defined as AE, which does not necessarily have a causal relationship with the intervention. AEs possibly happened during this study mainly include: (1) gastroenterological abnormalities (nausea, vomit, gingival hyperplasia, upper abdominal pain, diarrhoea); (2) abnormal liver function; (3) blood and lymphatic system disorders (anaemia, thrombocytopaenia and bone marrow failure); (4) neurological abnormalities (tremor, drowsiness, confusion); (5) skin and subcutaneous tissue disorders (alopecia, angioneurotic oedema, rash, toxic epidermal necrolysis and Steven-Johnson syndrome). All death due to the progression of AEs will be defined as severe adverse event (SAE). The details of all AEs and SAEs should be reported to DSMB in the corresponding case report form. For SAEs, the report must be submitted within 24 hours.

Sample size estimates

Previous studies reported that patients with aSAH have a 15.3% risk of seizures,9 and anticonvulsant (levetiracetam) treatments reduce in-hospital seizure rate to 9% in the short duration (3 days) group compared with 2% in the extended duration (until discharge) arm.21 We assume that sodium valproate prophylaxis could reduce the seizure incidence from 15.3% to 3%. The sample size was calculated based on an alpha of 0.05, statistical power of 90% and 10% loss to follow-up, which yielded 182 patients (91 in each arm).

Statistical analyses

All analyses are by intention-to-treat. Categorical endpoints (eg, seizure rate, AEs, mortality, complications) will be compared using χ² tests. Continuous and scale variables will be analysed by non-parametric (Wilcoxon rank sum test) or parametric (Student’s t-test) test according to the distribution of different data. Time-to-event outcomes (time to seizure) will be analysed using the log-rank test, with Kaplan-Meier survival curves. Cox regression will also be performed. Subgroup analysis based on age (≥70), size of aneurysm, location of aneurysm, rebleeding will also be performed.