Stroke is a significant cause of morbidity and disability worldwide. As the population
ages, the economic impact of this condition is becoming very significant [1]. In the UK
alone, the stroke estimated cost is £26 billion a year [2]. A stroke occurs every 5 min,
which is more than 100,000 strokes in the UK each year [3]. Stroke is a leading cause of
disability in the UK - almost two-thirds of stroke survivors in England, Wales and
Northern Ireland leave the hospital with a disability [4].
The two main types of stroke are ischaemic (as a result of a blocked blood vessel) and
haemorrhagic (due to bleeding in the brain). Acute ischaemic stroke (AIS) represents the
most prevalent form of stroke (85%) and has been the target of numerous unsuccessful
clinical drug trials. Therefore, AIS poses a major therapeutic challenge. The primary
treatment comprises of intravenous delivery of thrombolytic agents such as Tissue
Plasminogen Activator (tPA) and endovascular treatment (EVT) aiming at recanalization of
an occluded vessel, and is usually only effective in patients who present within 4.5
hours of the onset of symptoms and 24 hours, for tPA and EVT, respectively [5, 6]. Yet,
tPA has limited benefit in AIS patients with relatively large vessel occlusion (LVO),
with only about 25% of the population achieving good clinical outcomes. Therefore, more
recently, patients with proximal LVO have been treated with mechanical thrombectomy (MT),
an endovascular technique that enables the restoration of blood flow by removing the
obstructing blood clot from the affected artery with greater efficacy and a longer
treatment window [6].
The standard treatment provided at present to AIS patients in the NHS in the post-acute
phase consists of limited neurorehabilitation: 3 x 40 minute-long sessions with a
therapist each week for 6 weeks in the acute stroke unit. This is divided between
occupational therapy, physiotherapy, and speech and language therapy. Early intensive
therapy in adults with AIS has been shown to have beneficial effects[7]. The current NHS
rehabilitation standard may be suboptimal, as studies in the literature such as Zhu et
al. found increased gains in patients after intensive (4 hours per day) versus standard
(2 hours per day) rehabilitation support [8].
About 80% of acute stroke patients suffer from upper extremity (UE) motor impairments,
and of those, hemiparesis is the most commonly exhibited damage. Upper limb complications
commonly involve impaired sensation, movement and coordination. Among those, more than
50% retain some degree of hemiparesis months after stroke and remain unable to use their
affected UE, which leads to impaired activities of daily living (ADL) and therefore
compromised quality of life (QoL) [9, 10].
Souvenaid® (Nutricia, N.V., Zoetermeer, The Netherlands), is a commercially available
food for special medical purpose that is used as a daily Oral Nutritional Supplement
(ONS). It contains a specific nutrient combination, named Fortasyn Connect (FC), which
has been shown to enhance synapse formation and function [11]. The product is currently
used in the management of early Alzheimer's disease, as a specialised medical nutrient
support, and it has been shown to preserve functional brain network organization, using
electroencephalography (EEG), and also reduce cognitive decline [12, 13]. It is well
established that stroke also disrupts complex neural network structure, and this is
linked to disrupted neurological function. EEG is a non-invasive method of assessing
cortical connectivity with high temporal sensitivity and it can be used to monitor neural
network changes resulting from brain insults such as ischaemic stroke [14, 15]. In
particular, Liu and colleagues recently showed that AIS patients display a weakened
cortical connectivity, suggesting functional impairment in cortical information
transmission [16].
FC is a specialised medical food which contains nutrients critical for brain phospholipid
synthesis, specifically, the active components are docosahexaenoic acid (DHA),
eicosapentaenoic acid (EPA), uridine monophosphate, choline, phospholipids, selenium,
folic acid, and vitamins B12, B6, C and E [11, 12]. Work from our research group shows
that in an animal model of traumatic brain injury (controlled cortical impact in adult
mice), a diet enriched with FC leads to improved sensorimotor and cognitive outcomes, as
well as improved neurogenesis [17]. Another study, using the transient middle cerebral
artery occlusion (tMCAo) experimental model of stroke, showed that animals receiving a
diet supplemented with FC after stroke had decreased levels of neuroinflammation,
improved structural connectivity and improved motor function, therefore indicating that
this medical food has therapeutic potential in ischaemic stroke [18]. These independent
sets of animal data in two models of acquired brain injury, show that a nutritional
intervention with a specialised medical food could potentially improve neurological
recovery and protect the nervous tissue after injury. This has led to design the present
proposal for a feasibility study using Souvenaid in ischaemic stroke.
Preclinical data
A control diet or a diet enriched in FC were given for 35 days following injury in a
mouse model of ischaemic stroke, induced by tMCAo. Mice receiving the FC diet showed
improved sensorimotor function, enhanced structural connectivity, reduced
neuroinflammation and beneficial effects on cerebral blood flow (CBF). This data indicate
that FC administration has beneficial effects on both functional and structural indices
of recovery and therefore a significant therapeutic potential in ischaemic stroke [18].
Clinical data
In a first proof-of-concept study, the food for special medical purpose ONS product was
safe and well tolerated and improved memory performance in mild Alzheimer's disease
patients, after 12 weeks of consumption[19]. In a second randomised, controlled,
double-blind, parallel-group trial, 259 mild Alzheimer's disease patients from 27 centres
in six European countries received the ONS product or an isocaloric control drink for 24
weeks. Again, Souvenaid significantly improved memory performance and preserved the
organisation of brain networks as measured with EEG [20], bolstering the hypothesis that
Souvenaid positively affects synaptic integrity and function [21]. Furthermore, the
recent LipiDiDiet study, was a 24-month randomised, controlled, double-blind,
parallel-group, multi-centre trial. The trial enrolled individuals with prodromal
Alzheimer's disease. Souvenaid was shown to diminish the cognitive decline expected in
the patients with dementia. A significant difference in the loss of hippocampal volume
(associated with memory deficits) was also seen in the treated group versus the control
group [12]. The significant positive impact of Souvenaid was further supported by the
3-year extension data [12]. In these trials, Souvenaid was safe and well tolerated.
Currently, a similar study providing Souvenaid ONS to patients with traumatic brain
injury (IRAS ID 273132) is performed in the same Trust as proposed in this trial. So far,
patients tolerate the ONS well and are fine with having a daily ONS
Rationale
The rationale for the proposed study is to provide AIS patients with a single daily
supplementation of Souvenaid or standard of care to investigate the feasibility of this
intervention, in preparation for a future larger trial in this population of patients.
Based on our preclinical data we hypothesise that augmenting nutrition with an ONS
product containing FC has the potential to support neuroplasticity post-injury and
improve functional recovery after AIS.
The primary endpoint investigated in this study would be the feasibility of using this
ONS product in stroke patients. Secondary endpoints will determine changes in nutritional
status, QoL status and ADL, as well as fatigue levels. Other secondary endpoints will
include cognitive recovery scores and plasma levels of specific biochemical markers
associated with neural injury and nutritional status. Stroke is associated with increased
risk of infections, and FC contains long-chain omega-3 fatty acids which have been shown
to generate powerful pro-resolving mediators which have the potential to reduce
inflammation and infection rate [22-24]. We will assess the level of C-reactive protein
in patients and monitor their infections, with focus on pneumonia and urinary tract
infections (UTI) [25]. All these secondary endpoints have been chosen in order to
generate preliminary data and to inform and optimise the design of future trials.