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.
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.
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.
