Translating experimental stroke therapy to patients: determination of optimal dosing and biological efficacy of IL-1ra

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

Stroke is the third biggest killer world wide and the most common cause of adult disability in the UK. Deaths caused by stroke will nearly double in the next decade. Despite this, there are few treatments.

Many studies of potential new treatments have failed, some because it was not fully understood how the treatment worked and how best to give it.

A stroke occurs when the blood supply to the brain is disrupted. This causes inflammation in the brain. We have been working on a possible new treatment for stroke, called IL-1ra. IL-1ra is a copy of a naturally occurring chemical that blocks inflammation and is already used in diseases like rheumatoid arthritis. It would be given soon after a stroke and would work by protecting brain cells from damage.

We have given IL-1ra to a small number of stroke patients to check that is safe. We are planning to move on to the next stage of developing the treatment (Phase III study) to see how effective it is. Before we do this we want to be sure we are giving the right dose, in the best way.

We have completed a study which looked at how the IL-1ra gets into brain from the blood stream. This study was done in patients with subarachnoid haemorrhage (SAH) who had a tube draining fluid (cerebrospinal fluid, CSF) from around the brain to relieve pressure. We collected samples of the CSF to measure IL-1ra and found that it can take up to four hours to reach protective levels. After a stroke we need to get enough IL-1ra into the brain as quickly as possible to protect it from damage.

In the proposed studies we want to:
1. Give different amounts of IL-1ra to find the dose that gets enough IL-1ra into the CSF quickly.
2. Measure the effect of IL-1ra on inflammation in the brain of patients with SAH, using the dose found in study 1. This will be done by measuring markers of inflammation in samples of CSF and from within the brain (using a technique called microdialysis).

3. Give IL-1ra to patients with stroke to check whether it is having the same effect as in patients with SAH.

This will ensure that we design the safest and most effective clinical trial that we can.

Technical Summary

This proposal addresses one of the greatest unmet clinical needs, cerebral ischaemia, and is therefore relevant to stroke, haemorrhage, brain injury, vascular dementia and birth hypoxia.

There is now extensive evidence that the cytokine interleukin-1 (IL-1) is a key mediator of experimentally-induced cerebral ischaemia. The endogenous IL-1 receptor antagonist (IL-1ra) markedly reduces diverse forms of ischaemic, traumatic and excitotoxic brain injury in rodents and is effective when given some hours after the injury. As a result of these findings we have undertaken a small Phase II study of IL-1ra in acute stroke. IL-1ra was safe, markedly inhibited markers of peripheral inflammation and showed potentially promising effects on outcome. We have demonstrated that iv treatment with IL-1ra in SAH patients results in CSF levels that are at least as high as those found in rodents when neuroprotection is seen.

This proposal addresses two questions that are critical before a full Phase III efficacy trial of IL-ra is undertaken in stroke and/or SAH:

What is the optimal dosing regime to achieve the most rapid levels of IL-1ra in the CNS?
Does IL-1ra inhibit CNS inflammation? This will provide important proof of principle for more extensive studies.

We will undertake most studies on SAH patients for pragmatic reasons.
1. We will compare CSF levels of IL-1ra administered iv in different doses to SAH patients.
2. We will study inflammatory markers in CSF, in brain tissue (by microdialysis) and in blood in SAH patients given IL-1ra (dose determined by 1) or placebo.
3. We will repeat study 2 in a small number of stroke patients.

Given the successful studies we have undertaken to date and the combined expertise of the applicants and collaborators, we believe that the studies proposed are highly feasible and will determine whether a full Phase III efficacy study is justified and how such a study might best be designed.
 
Description Neurosurgical Representative on the current NICE Committee revising the NICE guidelines for the early management of head injury in adults and children (due to be published published in 2013/4)
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Head injury guidelines
 
Description Update to Trust EVD protocol
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact During the course of the PK study it was found that infection rates for SAH patients with external ventricular drains (EVDs) inserted was lower than the clinical average. This led to our researchers updating the EVD protocol for the local NHS Trust. Once approved by The Clinical Effectiveness Committee it will allow senior nurses as well as medics to sample from EVDs and standardize practice across Neuroscience. Nov. 2010: This has now been approved and research staff are responsible for training of clinical staff. Furthermore, nursing staff are now working to this protocol and have developed a care pathway for patients with EVDs. A re-audit of infection rates in patients with EVDs is planned for 2011. Nov. 2011: now published - see publications. Further work is ongoing on CNS infection and relationship with predictive value of interleukin-6.
 
Description Clinical Lectureship in Neurosurgery (University of Manchester and part MRC DCS grant)
Amount £70,000 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start  
 
Description Developmental Clinical Studies
Amount £600,000 (GBP)
Funding ID G1001252 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2011 
End 04/2014
 
Description MRC Models of Disease Grant
Amount £640,000 (GBP)
Funding ID G0801040 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2008 
End 08/2012
 
Description NIHR BRC
Amount £1,892,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2017 
 
Description 13C-labelled microdialysis 
Organisation University of Calgary
Department Section of Neurosurgery
Country Canada 
Sector Academic/University 
PI Contribution 13C labelling studies of brain metabolism using microdialysis in traumatic brain injury patients.
Collaborator Contribution Our collaborator has visited us in Cambridge on a Visiting Fellowship (awarded by the Canadian Institute of Health Research). The collaboration is ongoing and our collaborator is a Co-investigator on a current MRC Research Grant (PI: Peter Hutchinson, G1002277 ID 98489).
Impact Publication: Gallagher CN, Carpenter KL, Grice P, Howe DJ, Mason A, Timofeev I, Menon DK, Kirkpatrick PJ, Pickard JD, Sutherland GR, Hutchinson PJ. The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study. Brain. 2009 Oct;132(Pt 10):2839-2849. PubMed PMID: 19700417.
Start Year 2006
 
Description British Neurosurgical Trainee Research Collaborative 
Organisation Society of British Neurological Surgeons
Country United Kingdom 
Sector Learned Society 
PI Contribution AK and PH led the efforts to establish the British Neurosurgical Trainee Research Collaborative. The BNTRC is a research network for trainees which will aim to develop, run and support neurosurgical trials.
Collaborator Contribution The SBNS has very generously supported this initiative since its inception.
Impact PMID: 22583319
Start Year 2012
 
Description British Neurotrauma Group 
Organisation Society of British Neurological Surgeons
Country United Kingdom 
Sector Learned Society 
PI Contribution Initiative to set up a special-interest group within the Society of British Neurological Surgeons
Collaborator Contribution Increasing understanding of the issues surrounding decompressive craniectomy in head injury
Impact The first academic meeting of the group took place in 2010 (October). The meeting was attended by neurosurgeons, neurorehabilitation consultants, endocrinologists, neurologists and specialist nurses.
Start Year 2008
 
Description Engineering - finite element analysis of decompressive craniectomy 
Organisation University of Cambridge
Department Department of Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution Increasing the understanding of the clinical consequences of brain deformation after craniectomy
Collaborator Contribution Finite element analysis of decompressive craniectomy
Impact Publications
Start Year 2010
 
Description International Multicentre Randomised Trial 
Organisation European Brain Injury Consortium (EBIC)
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution Study set-up, patient recruitment and data collection
Collaborator Contribution Patient recruitment
Impact Recruitment of 280 patients from 43 centres in 17 countries
 
Description International Multicentre Randomised Trial 
Organisation International Neurotrauma Society (INTS)
Country Hungary 
Sector Charity/Non Profit 
PI Contribution Study set-up, patient recruitment and data collection
Collaborator Contribution Patient recruitment
Impact Recruitment of 280 patients from 43 centres in 17 countries
 
Description International Multicentre Randomised Trial 
Organisation Society of British Neurological Surgeons
Country United Kingdom 
Sector Learned Society 
PI Contribution Study set-up, patient recruitment and data collection
Collaborator Contribution Patient recruitment
Impact Recruitment of 280 patients from 43 centres in 17 countries
 
Description Provision of Amgen IL-1RA for clinical studies 
Organisation Amgen Inc
Country United States 
Sector Private 
PI Contribution Carried out pharmacokinetic study to identify optimal dosing regime of IL-1RA in SAH patients.
Collaborator Contribution Provision of IL-1RA for clinical studies
Impact Pharmacokinetic study identified optimal dosing regime of IL-1RA in SAH patients to take forward to test efficacy in further trials. Phase II randomised controlled double blind trial (IL-1RA vs placebo) now completed in SAH patients (analysis in progress).
 
Description All types and numerous locations; numerous examples 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Numerous scientific, public and policy talks - too many to detail.

Significant press coverage
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Annual STARS lecture, Manchester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Annual STARS lecture to ~200 local sixth form and college students.
Title: 'A stroke of bad luck: Understanding brain disease' (targeted at A level Biology).

Not known.
Year(s) Of Engagement Activity 2011
 
Description Event for stroke patients and carers, Nov. 2010 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 10 stroke survivors/carers attended an event called "Stroke research - from test tube to treatment", which comprised talks from 3 researchers, spanning preclinical to clinical studies, and interacted with post-docs and students over various displays and refreshments. The feedback from attendees was mostly very positive and all but one expressed an interest in attending future events. The constructive feedback has made us re-evaluate what we want to achieve from such events and will inform future events.

We are re-evaluating the aims of such events and are planning further, larger events, taking into account the feedback received from this meeting. Specifically, we will be involved in a large event for World Stroke Day 2011, with our clinical colleagues.
Year(s) Of Engagement Activity 2010
 
Description Frontiers of Science talk, Uni of Manchester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Frontiers of Science talk delivered to ~150 undergraduate students from 1st year to 3rd year, followed by questions and discussion.
Title: "Flaming brains - new discoveries about brain disease"


No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Give approx. 10-12 public and schools lectures each year (too numerous to detail) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Give approx. 10-12 public and schools lectures each year (too numerous to detail)

Not possible to detail specific impacts - aim to increase interest in science, particularly in underprivileged areas. Often receive requests from school students wishing to do work experience in the lab, following a talk at their school (all of whom we aim to accommodate wherever possible).
Year(s) Of Engagement Activity 2009
 
Description Keynote lecture to Schools Science Conference 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Talk followed by Q&A session. Title: "A stroke of bad luck - new discoveries in the treatment of brain disease". Session: Science is the Future.
Venue : Royal College of Pathologists, London
Audience : 50 secondary year students from years 10-13 and their teachers

No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Lecture at the University of Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Talk title: "A stroke of bad luck: mechanisms and treatments for brain disease". For ~200 Uni staff and students. Followed by questions and discussion.

No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Numerous scientific, public and policy talks - too many to detail 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Numerous scientific, public and policy talks - too many to detail.

Significant press coverage
Year(s) Of Engagement Activity 2006,2007,2008
 
Description Presentation to Brain and Spinal Injury Charity (BASIC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact 50 members of the public and previous service users (patients and carers) received feedback from previous research studies, update on current research and details of further research plans.

All attendees have and wish to continue to contribute to the development of patient information sheets for clinical studies, which is invaluable in attaining ethical approval for clinical research studies.
Year(s) Of Engagement Activity 2010
 
Description World Stroke Day 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact World Stroke Day event in Oct. 2011 organised by our clinical colleagues. The clinical investigator Dr Tyrrell presented the results of the clinical study funded by this grant. The audience comprised ~180 stroke patients and their carers, healthcare professionals and associated charities/organisations.

Not known.
Year(s) Of Engagement Activity 2011