Plain English Summary
Background and study aims
Subarachnoid haemorrhage (SAH) is a bleed onto the surface of the brain. It is usually caused when a weakness (aneurysm) in the wall of a blood vessel within the brain suddenly bursts. It affects up to 6,000 people every year in the UK. Up to half of all patients do not survive long enough to receive hospital treatment and those who do survive, often suffer long-term issues that impact on their daily life. In the hours and days after SAH, patients are at risk of further brain damage due to inflammation (swelling). A protein called interleukin-1 (IL-1) is the main culprit and this triggers a number of other chemicals in the circulation which may lead to physical symptoms similar to stroke but can also cause problems with language, mood, anxiety and fatigue all of which impact most on recovery and returning to work. The effect of IL-1 can be blocked, reduced or even reversed by another protein present naturally in our body; interleukin-1 receptor antagonist (IL-1Ra). A company has produced a man-made version of IL-1Ra, which has been used for many years as an anti-inflammatory treatment for rheumatoid arthritis. Inflammation occurs very early after the initial haemorrhage and can continue for up to 21 days, which means IL-1Ra should be given early and through the risk period to prevent or reduce these symptoms. Our group has successfully tested IL-1Ra in patients with subarachnoid haemorrhage and found it reduces inflammation in the circulation and brain and we now want to establish whether IL-1Ra improves recovery after subarachnoid haemorrhage. The aim of this study is to treat patients with SAD using IL-1Ra subcutaneously twice daily to see if this can improve clinical outcomes.
Who can participate?
Adults aged 18 and older who have SAH.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive subcutaneous injections of IL-1Ra twice daily for up to 21 days from the onset of their symptoms. Those in the second group receive a placebo (a dummy) twice daily for 21 days. All participants continue to receive the standard care for subarachnoid haemorrhage and participation in this study will not affect or delay this care. Participants provide blood samples before the treatment, and after 3-5 days to measure levels of inflammatory markers in the blood. Participants are followed up for safety for 30 days and are followed up for six months to assess the impact of the treatment.
What are the possible benefits and risks of participating?
As this is a phase III study it will be made clear to participants that there is no evidence of benefit at this stage. Participants will also be advised that as this study is double-blind and randomised and it will not be known if they will receive study drug or placebo. Evidence from earlier phase studies showed that the study drug reduces inflammation associated with SAH and is safe to use. The results of this study will provide evidence whether reducing inflammation improves outcome and participants may be helping to provide the evidence that may change treatment for SAH in the future.
Where is the study run from?
This study is being run by the University of Manchester (UK) and takes place in hospitals in the UK.
When is the study starting and how long is it expected to run for?
July 2015 to October 2022
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
Ms Helen Bradley
helen.bradley@christie.nhs.uk
Trial website
Contact information
Type
Scientific
Primary contact
Ms Helen Bradley
ORCID ID
Contact details
Clinical Trial Project Manager
Manchester Academic Health Science Centre Trial Coordination Unit (MAHSC-CTU)
Block C Withington Hall
The Christie Hospital NHS Foundation Trust
Wilmslow Road
Manchester
M20 4BX
United Kingdom
+44 161 918 2142
helen.bradley@christie.nhs.uk
Additional identifiers
EudraCT number
2016-003725-42
ClinicalTrials.gov number
Protocol/serial number
35757
Study information
Scientific title
Does Interleukin-1 Receptor Antagonist Improve Outcome following aneurysmal Subarachnoid Haemorrhage (aSAH)? A Phase III trial
Acronym
SC IL-1Ra in SAH - phase III trial
Study hypothesis
Treatment with IL-1Ra subcutaneously (SC) twice daily to patients with aneurysmal subarachnoid haemorrhage will improve clinical outcome at 6 months.
Ethics approval
North West – Haydock Research Ethics Committee, 03/11/2017, ref: 17/NW/0581
Study design
Randomised; Interventional; Design type: Treatment, Drug
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Specialty: Stroke, Primary sub-specialty: Hyperacute; UKCRC code/ Disease: Stroke/ Cerebrovascular diseases
Intervention
This is a double-blind, placebo-controlled trial. Patients with aneurysmal subarachnoid haemorrhage receive subcutaneous injections of IL-1Ra or placebo twice daily for up to 21 days from the onset of their symptoms. Blood samples are taken before the start of the intervention and after 3-5 days to measure levels of inflammatory markers in the blood. Participants are followed up for safety until day 30 after the start of the intervention and are followed up after six months to assess the impact of the intervention on clinical outcome.
Intervention type
Other
Phase
Phase III
Drug names
Primary outcome measures
Clinical outcome is measured using the modified Rankin Scale (mRS) questionnaire at 6 months.
Secondary outcome measures
1. Mood is measured using the Hospital Anxiety and Depression Scale questionnaire at 6 months
2. Fatigue is measured using the GM-SAT Fatigue question and Fatigue Severity Score questionnaire at 6 months
3. Quality of life is measured using the EQ-5D-5L questionnaire at 6 months
Overall trial start date
15/07/2015
Overall trial end date
31/10/2022
Reason abandoned
Eligibility
Participant inclusion criteria
1. Patients with CT positive spontaneous SAH admitted to a participating neurosurgical centre where written informed consent can be obtained and study drug can be administered within 72 hours of ictus
2. No concomitant health problems that, in the opinion of the PI or designee, would interfere with participation, administration of study drug or assessment of outcomes including safety
3. Willing and able to give informed consent or consent available from a patient representative for trial inclusion including agreement in principle to receive study drug and undergo all study assessments
4. Male or female aged 18 years or above
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 1000; UK Sample Size: 1000
Participant exclusion criteria
1. Unconfirmed or uncertain diagnosis of spontaneous SAH
2. Known active tuberculosis or active hepatitis
3. Known active malignancy
4. Neutropenia (ANC <1.5 x 109/L )
5. Abnormal renal function (creatinine clearance or estimated Glomerular Filtration Rate (eGFR) < 30 ml/minute) documented in the last 3 months prior to this SAH
6. Live vaccinations within the last 10 days of this SAH
7. Previous or concurrent treatment with IL-1Ra known at the time of trial entry or previous participation in this trial
8. Previous or current treatment with medication suspected of interacting with IL-1Ra, listed in the drug SmPC
9. Known to have participated in a clinical trial of an investigational agent or device in the previous 30 days or 5 half-lives of enrolment (whichever is longer) of ictus, or for the period determined by the protocol of the trial / study the patient has taken part in
10. Known to be pregnant or breast feeding or inability to reliably confirm that the patient is not pregnant
11. Clinically significant serious concurrent medical condition, pre morbid illnesses, or concurrent serious infection, at the PI’s (or designee’s) discretion, which could affect the safety or tolerability of the intervention
12. Known allergy to IL-1Ra or any of the excipients listed in the drug SmPC
13. Known allergy to other products that are produced by DNA technology using the micro-organism E. coli (e.g. E.coli derived protein)
Recruitment start date
31/05/2018
Recruitment end date
30/11/2021
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Salford Royal NHS Foundation Trust
Stott Lane
Salford
M6 8HD
United Kingdom
Trial participating centre
Royal Stoke University Hospital
Newcastle Road
Stoke-on-Trent
ST4 6QG
United Kingdom
Trial participating centre
Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom
Trial participating centre
Hurstwood Park Neurosciences Centre
Lewes Road
West Sussex
RH16 4EX
United Kingdom
Trial participating centre
National Hospital for Neurology and Neurosurgery
Queen Square
London
WC1N 3BG
United Kingdom
Trial participating centre
South West Neurosurgery Centre
Derriford Hospital
Derriford Road
Crownhill
Devon
Plymouth
PL6 8DH
United Kingdom
Trial participating centre
Wessex Neurological Centre
Southampton General Hospital
Tremona Road
Hampshire
Southampton
SO16 6YD
United Kingdom
Trial participating centre
University Hospital of Wales
Heath Park
Cardiff
CF14 4XW
United Kingdom
Trial participating centre
Western General Hospital
Crewe Road South
Edinburgh
EH4 2XU
United Kingdom
Funders
Funder type
Government
Funder name
National Institute for Health Research
Alternative name(s)
NIHR
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Publication in a high-impact peer reviewed journal is planned and is likely to be in the second half of 2023.
IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
01/12/2023
Participant level data
To be made available at a later date
Results - basic reporting
Publication summary