Can IL-1ra reduce inflammation and improve clinical outcome following aneurysmal SAH?
| ISRCTN | ISRCTN12961797 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12961797 |
| EudraCT/CTIS number | 2016-003725-42 |
| IRAS number | 214739 |
| ClinicalTrials.gov number | NCT03249207 |
| Secondary identifying numbers | CPMS 35757, IRAS 214739 |
- Submission date
- 04/12/2017
- Registration date
- 14/12/2017
- Last edited
- 29/11/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Plain English summary of protocol
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 April 2024
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
Jane Pearson, SCIL@manchester.ac.uk
Contact information
Scientific
Clinical Trial Manager
Manchester Clinical Trials Unit
The University of Manchester
Jean McFarlane Building
Oxford Road
Manchester
M13 9PL
United Kingdom
| Phone | +44 (0)161 918 2142 |
|---|---|
| SCIL@manchester.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Does Interleukin-1 Receptor Antagonist Improve Outcome following aneurysmal Subarachnoid Haemorrhage (aSAH)? A Phase III trial |
| Study acronym | SC IL-1Ra in SAH - phase III trial |
| Study objectives | Treatment with IL-1Ra subcutaneously (SC) twice daily to patients with aneurysmal subarachnoid haemorrhage will improve clinical outcome at 6 months. |
| Ethics approval(s) |
Approved 03/11/2017, North West - Haydock Research Ethics Committee (3rd Floor - Barlow House, 4 Minshull Street, Manchester, M1 3DZ, United Kingdom; +44 (0)20 7104 8137; haydock.rec@hra.nhs.uk), ref: 17/NW/0581 |
| Health condition(s) or problem(s) studied | Stroke |
| 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 |
| Primary outcome measure | 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 study start date | 15/07/2015 |
| Completion date | 30/04/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 1000; UK Sample Size: 1000 |
| Total final enrolment | 612 |
| Key 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 |
| Key exclusion criteria | Current participant exclusion criteria as of 14/08/2023: 1. Unconfirmed or uncertain diagnosis of spontaneous SAH 2. Known active tuberculosis or active hepatitis 3. Known active malignancy 4. Known Still's Disease 5. Neutropenia (ANC <1.5 x 109/L ) 6. Abnormal renal function (creatinine clearance or estimated Glomerular Filtration Rate (eGFR) < 30 ml/minute) documented in the last 3 months prior to this SAH 7. Live vaccinations within the last 10 days of this SAH 8. Previous or concurrent treatment with IL-1Ra known at the time of trial entry or previous participation in this trial 9. Current treatment with TNF antagonists 10. Known to have participated in a clinical trial of an investigational agent or device in the 30 days prior to ictus 11. Known to have participated in a clinical trial of an investigational agent or device within 5 half-lives (of the previous agent or device) prior to ictus 12. Known to be pregnant or breastfeeding or inability to reliably confirm that the patient is not pregnant 13. Clinically significant serious concurrent medical condition, pre-morbid illnesses, or concurrent serious infection (including confirmed or suspected COVID-19 infection), at the PI’s (or designee’s) discretion, which could affect the safety or tolerability of the intervention 14. Known allergy to IL-1Ra or any of the excipients listed in the drug SmPC 15. Known allergy to other products that are produced by DNA technology using the microorganism E. coli (e.g. E.coli derived protein) 16. Current treatment with IL-6 or IL-1 inhibitors or drugs affecting the IL-1 axis 17. History of DRESS syndrome Previous 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) |
| Date of first enrolment | 31/05/2018 |
| Date of final enrolment | 30/09/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Stoke-on-Trent
ST4 6QG
United Kingdom
Sheffield
S10 2JF
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Stott Lane
Salford
M6 8HD
United Kingdom
London
WC1N 3BG
United Kingdom
Derriford Road
Plymouth
PL6 8DH
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Leeds
LS1 3EX
United Kingdom
London
SW17 0QT
United Kingdom
Fazakerley
Liverpool
L9 7LJ
United Kingdom
Eastern Road
Brighton
BN2 5BE
United Kingdom
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
London
W6 8RF
United Kingdom
80 Newark Street
London
E1 2ES
United Kingdom
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom
Sharoe Green Lane
Fulwood
Preston
PR2 9HT
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Sponsor information
University/education
Oxford Road
Manchester
M13 9PL
England
United Kingdom
"ROR" |
https://ror.org/027m9bs27 |
|---|
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/08/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Current publication and dissemination plan as of 14/08/2023: Publication in a high-impact peer reviewed journal is planned and is likely to be in the second half of 2024. Previous 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. The study protocol is available at https://www.journalslibrary.nihr.ac.uk/programmes/eme/1420907/#/ (added 04/06/2021) |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol file | version 8.0 | 04/06/2020 | 14/08/2023 | No | No |
| Protocol file | version 9.0 | 13/03/2023 | 13/10/2023 | No | No |
Additional files
Editorial Notes
29/11/2023: The study contact was updated.
13/10/2023: The following changes have been made:
1. Uploaded protocol (not peer reviewed).
2. The IRAS number was added.
3. The total final enrolment was added.
14/08/2023: The following changes have been made:
1. The participant exclusion criteria were changed.
2. Northern Care Alliance NHS Foundation Trust, National Hospital for Neurology & Neurosurgery, Plymouth Hospital, University Hospital Southampton NHS Foundation Trust, Leeds General Infirmary, St George's Hospital, The Walton Centre NHS Foundation Trust, Brighton and Sussex University Hospitals NHS Trust, Nottingham University Hospitals NHS Trust, Charing Cross Hospital, Barts Health NHS Trust, Southmead Hospital, Lancashire Teaching Hospitals NHS Foundation Trust and Addenbrookes were added as study participating centres.
3. Salford Royal NHS Foundation Trust, Hurstwood Park Neurosciences Centre, National Hospital for Neurology and Neurosurgery, South West Neurosurgery Centre, Wessex Neurological Centre, and Western General Hospital were removed as study participating centres.
4. The publication and dissemination plan was changed.
5. Uploaded protocol (not peer reviewed).
11/04/2022: The following changes have been made:
1. The recruitment end date has been changed from 31/03/2022 to 30/09/2023.
2. The overall trial end date has been changed from 31/10/2022 to 30/04/2024 and the plain English summary updated accordingly.
3. The intention to publish date has been changed from 01/12/2023 to 30/08/2025.
4. The scientific contact's details have been updated.
26/01/2022: The study contact has been updated and the plain English summary has been updated accordingly.
20/09/2021: Internal review.
04/06/2021: The following changes have been made:
1. The trial website has been added.
2. The ClinicalTrials.gov number has been added.
3. The publication and dissemination plan has been updated.
23/03/2021: The primary contact was updated.
28/07/2020: The recruitment end date has been changed from 30/11/2021 to 31/03/2022.
12/05/2020: The public contact has been updated and the plain English summary has been updated accordingly.
29/03/2019: The condition has been changed from "Specialty: Stroke, Primary sub-specialty: Hyperacute; UKCRC code/ Disease: Stroke/ Cerebrovascular diseases" to "Stroke" following a request from the NIHR.
05/12/2018: Contact details updated.
