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

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.

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.