Stem cell Trial of recovery EnhanceMent after Stroke 2 (STEMS 2) pilot randomised controlled trial

Lead Research Organisation: University of Nottingham
Department Name: Sch of Medical & Surgical Sciences

Abstract

Disordered movement is a common result of stroke and causes considerable physical disability and distress. Stem cells are a potential source of new brain and supporting cells, either by directly changing into the different cell types, or by stimulating local brain stem cells to change. Bone marrow stem cells (so-called CD34+ cells) may be moved into the blood circulation using granulocyte-colony stimulating factor (G-CSF), a naturally occurring hormone which controls certain bone marrow cells. 
We have previously completed a pilot randomised trial of G-CSF in 36 patients with recent stroke; G-CSF increased blood CD34+ cell counts by up to ten times depending on dose. G-CSF appeared safe and we now need to explore how the increase in circulating CD34+ cells might improve outcome after stroke. 
We have started a second pilot trial in 60 patients recruited 7 days after stroke onset to further assess the effects of G-CSF on safety. We are using magnetic resonance imaging of the brain to assess whether the site of damage reduces in size, whether cell content recovers in this area, whether connections between cells re-develop, whether the blood supply in this area improves, and whether CD34+ cells can be tracked moving to the damaged stroke region. If patients die, examination of the brain under a microscope will be performed assessing whether CD34+ stem cells are present in area of the stroke. 
If this study supports the idea that G-CSF may aid recovery after stroke, the results will help in the design of future trials of G-CSF in recent stroke. Even if the trial shows no effect, lessons from the study will provide useful information on how future trials of stem cells might be performed. If subsequent trials are positive, routine use of G-CSF would benefit patients and society, reduce load on carers and health care, and contribute to the UK Government‘s health strategy.

Technical Summary

Disordered motor function is a common result of stroke and causes considerable physical disability and social distress. Restoration of movement and motor function forms the focus of much rehabilitation based on physical and occupational therapy. Exogenous stem cells are a potential source of new neurones, glia and vascular cells, either directly through transdifferentiation, clonal expansion and neural integration, or through stimulating local neural progenitor cells. Endogenous CD34+ bone marrow cells may be mobilised with recombinant granulocyte-colony stimulating factor (G-CSF). We recently completed a phase IIa dose-escalation randomised placebo-controlled trial of G-CSF in 36 patients with sub-acute ischaemic stroke; G-CSF increased circulating CD34+ cell counts ten-fold in a dose-dependent manner. Intervention was apparently safe (although the infection rate was non-significantly higher), tolerated and feasible to administer. Potential mechanisms by which G-CSF might work and further safety assessment is now required.

We propose performing a phase II trial in 60 patients with recent ischaemic stroke (~7 days post ictus) further assessing the effects of G-CSF (1E6 IU/kg subcutaneous daily, 5 days) on safety (infection, death, deterioration, recurrence). We will assess potential mechanisms of action and evidence of recovery with reduction in lesion size (magnetic resonance [MR] imaging using day 90 MR T2 ? baseline MR diffusion), recovery (MR spectroscopy of neuronal [NAA] and glia [myoinositol] content), enhanced connectivity (MR diffusion tensor imaging), increased perfusion (MR perfusion, surrogate for angiogenesis), and CD34+ migration to the brain (T2* weighting of CD34+ labeled cells); haemostasis (soluble coagulation and platelet factors); and functional outcome. If patients die, histological examination of the brain will be performed assessing the presence of stem cells in the region of the stroke. If these data support potential functional effects of G-CSF on recovery mechanisms, they will inform the design of future trials of G-CSF in subacute stroke; even if neutral/negative, they will provide useful information on how future trials of stem cell therapies in stroke might be performed. G-CSF is readily available, easy to administer and monitor, relatively inexpensive (and will come off patent shortly) and could be relevant to many patients with recent ischaemic stroke.

If phase II/III developments are positive, routine use of G-CSF would benefit patients and society, reduce load on carers and health care, and contribute to the UK Government‘s health strategy.

Publications

10 25 50
 
Title CD34 cell tracking 
Description First human study of labelling CD34 cells and tracking their potential movement into the brain using MRI 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact This is helping to develop future research strategies in the department. 
 
Description Clinical Tissues Laboratory, Pathology, Nottingham University Hospitals NHS Trust 
Organisation Nottingham University Hospitals NHS Trust
Department Pathology Department
Country United Kingdom 
Sector Hospitals 
PI Contribution Work from the STEMS2 trial was the first project to run in the Clinical Tissues Laboratory and played a major role in ensuring its opening. We have also collaborated with colleagues in the same department (Electron Microscopy) during this work
Collaborator Contribution An important role in providing an HTA licensed facility to label haematopoeitic (CD34) stem cells with iron in a sterile environment. We have ongoing work assessing the labelling properties of CD34 stem cells.
Impact Our work is not yet published. However, our collaboration was displayed at a local meeting (STEM poster networking event, STEM Wolfson Centre, University of Nottingham, 29th September 2009) in the form of an oral and poster presentation, and at a national meeting in the form of an oral presentation to the Stem Cell Users Group (SCUG, 4th December 2008)
Start Year 2007
 
Description STEM Wolfson Centre, University of Nottingham 
Organisation University of Nottingham
Department School of Clinical Sciences Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing research material on ongoing stroke subjects to aid the understanding of stem cells in human cerebral ischaemia.
Collaborator Contribution Contribution towards understanding the role of stem cells in the human brain
Impact Pummed ID 19061938
Start Year 2008
 
Description Nottingham Stroke Research Showcase 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Health professionals
Results and Impact A lecture to a group describing current thoughts on stem cell treatment in stroke and an introduction to "STEMS2", the ongoing clinical trial funded by the MRC. The audience included members from the Nottingham Stroke Consumer Group and allied health professionals including doctors, nurses, physiotherapists, occupational therapists and speech and language therapists.

Increased local awareness of ongoing research.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013
 
Description Talk at Stem Cell Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk by Prof Bath at Stem Cell Conference - Stem Cells in Stroke
Year(s) Of Engagement Activity 2017
 
Description UK Stroke Forum 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Health professionals
Results and Impact Poster presentation of the ongoing "STEMS2" trial to an audience of health professionals and lay members. Members of the press also attend this conference.

Increased public awareness of our ongoing research.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013