Does giving an anti-epileptic drug before surgery help prevent seizures in patients with glioma (a type of brain tumour) who have not previously had a seizure?
| ISRCTN | ISRCTN70051203 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN70051203 |
| ClinicalTrials.gov (NCT) | Nil known |
| Clinical Trials Information System (CTIS) | 2018-001312-30 |
| Protocol serial number | HTA 16/31/136 |
| Sponsor | Public Health Scotland |
| Funder | National Institute for Health Research |
- Submission date
- 10/07/2018
- Registration date
- 02/07/2019
- Last edited
- 04/07/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English summary of protocol
Background and study aims
Gliomas are the most common type of primary brain tumour, with about 6000 new cases each year in the UK. 1 in 5 patients (20%) with a suspected glioma will present with an epileptic seizure and be treated with an anti-epileptic drug (AED). 4 in 5 patients (80%) do not present with seizures. Up to half of these patients will develop epilepsy requiring AED over their lifetime. Seizures can cause anxiety, loss of independence, affect quality of life & sometimes threaten life. AEDs prevent seizures in 50% of patients with epilepsy and reduce the frequency and severity of seizures in a further 20-30%. Currently, some doctors prescribe AEDs to patients before neurosurgery for tumours, whilst others do not. Researchers need to find out whether AEDs are effective and worthwhile to give the best advice to surgeons and patients in future. Previous studies of AEDs to prevent seizures in patients with a brain tumour have not shown clear results. However, these studies have included tumour types where the risk of seizures is low and they used older AEDs that may interfere with chemotherapy used in brain tumours and have a high risk of side effects. The newer AED, levetiracetam, has fewer side effects and does not interfere with chemotherapy drugs. There is a balance of potential advantages and disadvantages for prescribing levetiracetam. The aim of this study is to find out whether giving patients with a suspected primary brain tumour (cerebral glioma), who have never had a seizure, levetiracetam before surgery to see if it will help prevent them from developing seizures. This will help to give neurosurgeons in the UK the best advice about how to treat patients with a cerebral glioma.
Who can participate?
Patients due to have surgery who have recently been diagnosed with a possible brain tumour, and who have never had an epileptic seizure
What does the study involve?
Participants have a series of tests and examinations to confirm that they are eligible. They are then randomly allocated into two groups. The first group receive levetiracetam daily for 1 year. The second group receive no anti-epileptic drug; this is currently normal practice. Participants are contacted by the trials research nurse monthly by phone to check about any seizures or side effects. If there is a seizure, participants are asked to contact their usual treating team. A neurologist reviews the participant to confirm whether a seizure has occurred. Participants who have a seizure are asked to complete a seizure diary card and questionnaire about the severity of their seizure. All participants are asked to complete questionnaires about their symptoms and possible side effects at entry into the study and every 3 months for a minimum of 1 year. There is no need for any additional blood tests or additional hospital visits. Participants are able to continue on levetiracetam at the end of the study or come off it if they wish.
What are the possible benefits and risks of participating?
It is not known whether there will be a direct benefit to the participants. The researchers hope to be able to find out if taking levetiracetam before surgery will have any effect on delaying, stopping or altering the severity of any seizure that happens after the surgery. Participants taking levetiracetam might expect a lower risk of developing seizures, although the size of this effect is as yet unknown. The results of the trial will hopefully allow the researchers to provide the best advice on preventing seizures in patients with suspected cerebral glioma. A disadvantage of taking part in the study is that participants could experience side effects of levetiracetam. The levetiracetam is given at a lower dose for the first two weeks before increasing to the required dose to help reduce the side effects.
Where is the study run from?
Scottish Clinical Trials Unit, Edinburgh (SCTRU) (UK)
When is the study starting and how long is it expected to run for?
February 2019 to November 2023
Who is funding the study?
The study is funded by the National Institute for Health Research (NIHR). UCB Pharma, the manufacturer of levetiracetam, have provided this drug free of charge for patients taking part in this study that are allocated to the levetiracetam group
Who is the main contact?
Mrs Tracy McEleney, Service Manager, Public Health Scotland (PHS) Research Office, Edinburgh (UK), phs.researchoffice@phs.scot
Contact information
Public
Public Health Scotland Research Office
Gyle Square
1 South Gyle Crescent
Edinburgh
EH12 9EB
United Kingdom
| Phone | +44 (0)131 275 6544 |
|---|---|
| phs.researchoffice@phs.scot |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Two-arm multicentre phase III randomised trial |
| Secondary study design | Randomised controlled trial |
| Study type | Participant information sheet |
| Scientific title | Seizure PRophylaxis IN Glioma (SPRING): a Phase III randomised trial comparing prophylactic levetiracetam versus no prophylactic antiepileptic drug in patients with newly diagnosed presumed supratentorial glioma |
| Study acronym | SPRING |
| Study objectives | There is no consensus regarding the need for prophylactic AEDs in newly-diagnosed suspected glioma patients who have not experienced seizures. Unfortunately, data regarding prophylactic AED use is scant and inconclusive. Most of the available evidence comes from older, small studies that enrolled patients with brain metastases and benign tumours in addition to gliomas. Furthermore, these studies universally evaluated prophylaxis with first-generation AEDs such as phenytoin, phenobarbital, carbamazepine, and valproic acid. These drugs have higher rates of early adverse effects (such as rash, haematological or liver upset) compared to levetiracetam, and they have important interactions with other drugs including corticosteroids and chemotherapeutics. Levetiracetam is an effective, safe, and well-tolerated medication. It has no known drug interactions and does not require serum level monitoring. It is however frequently associated with fatigue (15%), behavioural problems (13-38%) and problems with aggression. A definitive clinical trial is needed to determine whether the policy of prophylactic levetiracetam therapy reduces the risk of first seizures in this patient population. In addition, evaluation of the impact of levetiracetam on fatigue, behaviour and aggression is needed in this vulnerable population with already high rates of fatigue, cognitive and behavioural problems. There is some evidence that levetiracetam may worsen these symptoms. There is a need to study this area in a well-designed randomised controlled trial. |
| Ethics approval(s) | Approved 05/02/2019, East of England – Essex REC (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; Tel: +44 (0)207 104 8115; Email: nrescommittee.eastofengland-essex@nhs.net); REC ref: 18/EE/0389 |
| Health condition(s) or problem(s) studied | Glioma |
| Intervention | After a patient has consented to participate in the study and after ensuring that the patient meets all eligibility criteria, sites will randomise the patient using a web-based randomisation system. This will not be a blinded study and will not have placebo control and as such will be a "real world" study of prophylactic anti-epileptic drug (AED) vs no AED. Patients will be randomised into one of two arms: Group 1: Levetiracetam 500 mg twice daily for 2 weeks then increasing to 750 mg twice daily thereafter for 1 year. Patients should have a minimum of 2 doses of 500 mg prior to surgery. (In those with moderate chronic kidney disease stage 3 (estimated Glomerular Filtration Rate eGFR 30-59 mL/min/1.73m2) a starting dose of 250 mg twice a day for 2 weeks, then increasing to 500 mg twice a day thereafter). Group 2: no AED treatment (standard care) |
| Intervention type | Drug |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Levetiracetam |
| Primary outcome measure(s) |
Number of patients developing seizures measured using two-sided type I error level of 5% at 1 year |
| Key secondary outcome measure(s) |
1. Time to first seizure measured using accelerated failure time model at 1 year |
| Completion date | 02/11/2023 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | All |
| Target sample size at registration | 804 |
| Total final enrolment | 107 |
| Key inclusion criteria | Patients: 1. Patients with suspected cerebral glioma on MRI or CT 2. Capable of giving informed consent 3. Patients must be ≥16 years old 4. Patients must have a Karnofsky performance status of >60 5. Patients must be able to safely swallow pills 6. Planned surgery for presumed glioma (biopsy or resection) Carers: Capable of giving informed consent |
| Key exclusion criteria | Patients: 1. Pregnant 2. History of any type of seizure for at least 10 years prior to randomisation 3. Known Severe Chronic Kidney Disease (CKD4 - eGRR <30 ml/min) 4. Concomitant methotrexate 5. Concomitant Anti-Epileptic Drug (including use for other reasons (e.g. pain)) 6. Concomitant Benzodiazepines 7. Hypersensitivity to Levetiracetam |
| Date of first enrolment | 15/07/2019 |
| Date of final enrolment | 31/08/2022 |
Locations
Countries of recruitment
- United Kingdom
- England
- Scotland
Study participating centres
Edinburgh
EH4 2XU
United Kingdom
The Walton Centre
Lower Lane
Liverpool
L9 7LJ
United Kingdom
London
SE5 9RS
United Kingdom
Birmingham
B15 2WB
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Leeds
LS1 3EX
United Kingdom
Glasgow
G51 4TF
United Kingdom
London
W6 8RF
United Kingdom
Hull
HU3 2JZ
United Kingdom
Stoke-on-trent
ST4 6QG
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Eccles
Salford
M6 8HD
United Kingdom
Headington
Oxford
OX3 9DU
United Kingdom
Fulwood
Preston
PR2 9HT
United Kingdom
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Other |
| IPD sharing plan | All presentations and publications relating to the trial must be authorised by the Trial Management Group. The main trial results will be published in the name of the trial in a peer-reviewed journal, on behalf of all collaborators. The manuscript will be prepared by the Trial Management Group, representatives from SCTRU and high accruing clinicians. The trials offices and all participating centres and clinicians will be acknowledged in this publication. Any data that might detrimentally affect the progress of the trial will not be released prior to the end of the trial. No investigator may present or attempt to publish data concerning their patients, which is directly relevant to the questions posed in the trial, until the main results have been published. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
| Protocol file | version V5.1 | 04/02/2019 | 11/07/2019 | No | No |
| Study website | Study website | 11/11/2025 | 11/11/2025 | No | Yes |
Additional files
- ISRCTN70051203_PROTOCOL_V5.1_04Feb19pdf.pdf
- Uploaded 11/07/2019
Editorial Notes
04/07/2025: The following changes were made:
1. A study contact was updated.
2. The intention to publish date was changed from 01/12/2024 to 01/09/2025.
05/01/2024: The final enrolment number has been added.
27/12/2023: The following changes have been made:
1. The recruitment end date has been changed from 15/08/2022 to 31/08/2022.
2. The overall study end date has been changed from 30/12/2023 to 02/11/2023 and the plain English summary updated accordingly.
3. The intention to publish date has been changed from 01/06/2023 to 01/12/2024.
4. The pharmaceutical study type has been added.
5. The 'suspended' status has been removed, as it appears that the study was completed.
6. The study website has been added.
7. Addenbrooke's Hospital, Leeds General Infirmary, Queen Elizabeth University Hospital, Charing Cross Hospital, Hull Royal Infirmary, Royal Stoke University Hospital, University Hospital Southampton, Salford Royal Hospital, John Radcliffe Hospital and Royal Preston Hospital have been added to the study participating centres.
8. The sponsor has been changed from the Common Services Agency to Public Health Scotland.
05/12/2023: The study contact email was changed.
20/04/2020: Due to current public health guidance, recruitment for this study has been paused.
11/07/2019: Protocol file uploaded (not peer-reviewed).
12/06/2019: Trial's existence confirmed by the NIHR.
