Severity of impairment, age, and vascular territory are the three major reasons for disqualifying patients for screening in AIS studies. Find out more…

1. ACUTE ISCHEMIC STROKE
(AIS) TRIAL CONSIDERATIONS/
CHALLENGES
Prescreening Considerations
Severity of impairment, age, and vascular territory are the three major reasons for disqualifying
patients for screening in Acute Ischemic Stroke (AIS) studies.
Selecting patients with higher degrees of impairment improves measurement sensitivity, but also
limits the eligible population. Lowering the severity criterion broadens the eligibility and may also
increase enrollment. This should be considered as long as it is scientifically justifiable.
Including unique assessments (for example to measure motor activity) that are not routinely performed
in practice or are not well known to investigators as part of clinical research settings will require thorough
and proper raters training certification and periodic assessment.
The inclusion criteria of entering the study at a certain point after the onset of a stroke event should be
well assessed based on the Mechanism of Action (MOA), type of Investigational Product (IP), preclinical
data and severity of patient sub-population. This factor could be considered as one of potential challenges
to the sites’ availability and patient consent. The first hours of stroke onset are critical for the patient; the
patient’s family and intensive care unit (ICU) staff; and investigators have limited availability to focus on
the patient’s condition. Furthermore, the patient’s mental status and legal representative availability are
both limiting factors. Therefore, it becomes extremely relevant to select sites with well-established stroke
protocols, which in turn facilitate arterial recanalization within the narrow time window for recovery
of penumbral tissue. Highly specialized stroke units are best suited for the implementation of study
protocols for IP whose MOA requires administration during the hyper-acute stage. Depending on the
MOA e.g. for IP targeting neuronal plasticity, evaluation of expansion of entry window even for two to
three days might be warranted as it could have a tangible positive effect on enrollment.
Selecting the patient sub-populations targeting specific infarct location, severity and/or endpoints should
be based on the anticipated product impact. For example, limiting the enrollment to middle cerebral
artery (MCA) strokes is justified when the primary endpoint of a study is focused upon motor recovery
after stroke. For studies of IP targeting malignant MCA, a more suitable primary endpoint would be
functional status e.g. modified Rankin scale.
Site Selection Considerations
Sites should be selected based upon their experience and previous performance in similar stroke studies.
We would like to highlight the importance of study awareness by neurological personnel in addition to the
principal and sub-investigators. Stroke is a sudden onset medical emergency and patients need to receive
immediate medical care. Considering that a stroke can occur at any point in time throughout a week,
including out of hours and weekends, the study awareness by on-call neurologists and 24/7 stroke unit
personnel will help with recruitment. Those staff members will be able to identify eligible patients and
could start the discussion on the study with patients and the patient’s family. This could create interest in
participating in the study during non-office hours which can then be converted into screening in the time
frame indicated in the protocol.

2. Ideally, selected sites should have stroke units with well-established infrastructure and specialized
personnel while also providing adequate standards to offer to the patients from their acute admission
to the unit throughout the study. We suggest that when considering increasing the number of sites
in other geographical areas, focus should be upon sites with stroke units, and not general neurological
departments. A significant proportion of referral hospitals, especially neuro-specialized ones across the
globe, have stroke units.
In 1995 the European Federation of Neurological Societies (EFNS) made stroke treatment and prevention a
major policy issue and established a task force to develop guidelines for acute neurological stroke care for use by
neurologists throughout Europe and to be modified according to local and national requirements (European Journal
of Neurology (1997); 4, 435-441). By now, most of the European countries are familiarized with those guidelines; while
variations on standard of care (SOC) post-stroke are to be expected, including length of stay in the ICU, the principles
of pharmacological and rehabilitation intervention are similar. This suggests that a relative homogeneity in stroke
clinical studies can be achieved when including additional sites in U.S., Western/Eastern Europe.
Another factor impeding recruitment is the sites, participation in competing studies. The data surrounding the
number of competing studies should be analyzed as part of operational strategy development prior to finalizing
recruitment projections and study timelines.
It is essential to select the right country Principal Investigator (PI) who is well respected and recognized as a key
opinion leader (KOL) and subject matter expert (SME) in the region, and who can support sponsor and local sites with
recruitment challenges.
It is also worth considering that, despite the KOL being scientifically engaged, their sites might not always be the best
performers in clinical study conduct. To reach the patient communities and spread awareness, resourcing to SAFE
members could be an option in Europe. Please refer to the below link for a list of SAFE country members:
http://www.safestroke.eu/list-of-members/
For example, the SAFE member organization, the France-AVC (Association for assistance to patients and families of
stroke patients), performs the following services:
▶ Informs the public, public authorities, and the media about stroke
▶ Assists and supports patients and families of stroke patients
▶ Assists in the training of doctors and paramedics
▶ Assists with stroke research
Resourcing to a SAFE member organization may provide additional sites for feasibility consideration.
Uniformity of Assessments
Interrater reliability of a measure directly affects the power of a study to detect the effects of an intervention. The
standardization of administration technique of performance-based measures increases its reliability. Special attention
should be placed on the key assessment tool used for the primary endpoint in a study. For example if the Fugl-Meyer
Assessment Scale is selected, it has to be accounted that it is not used widely in routine practice and not included in
the majority of AIS studies. Thus there is a need to provide initial trainings and periodic re-trainings with various
approaches and tactics (e.g., Didactic materials, background on scales, procedures for administration and common
errors, scoring of ‘gold standard’ videos of administration on real patients and in-person assessment of administration
technique at the Investigator Meeting: role-play, etc.).
To support the efforts on minimizing the interrater variability, specialized vendors providing such sophisticated training
programs and certifications would be the right choice. The Covance team can recommend such vendors if needed.

3. Study Standardization Techniques
Neurological grading, scoring systems, functional outcome measures and neurophysiological and
radiological evaluations should be standardized across sites to minimize inter-site variability and to
preserve study integrity and data quality.
Trained and blinded examiners are to be used to achieve high inter-rater reliability. Strict adherence to the
rules around examiner training and limits on engagement with the rest of the study should be discussed
with the investigators.
Epidemiology of Stroke
It is important to review the data and literature for the epidemiology of the targeted type of stroke and infarct
location. For example, approximately 80 to 85 percent of strokes are ischemic strokes. Anterior circulation
ischemic stroke accounts for approximately 70 percent of all ischemic strokes. Occlusion of the MCA or its
branches is the most common type of anterior circulation infarct, accounting for approximately 90 percent of
infarcts and two thirds of all first strokes.
Based upon the Global Burden of Disease 2016 database, the Institute of Health Metrics and Evaluation portal
reports the risk of stroke is highest in Asia, Eastern Europe, followed by Western Europe, the rest of Europe
and North America.1
These important statistical determinants must be tempered by taking the following
into account: homogeneity of the Standard Of Care (SOC), competition by other studies, past experience from
public and commercial sources and especially database information from Xcellerate®
, a proprietary from
Covance on performance metrics, including enrollment, site startup times and others.
Patient and Caregiving Considerations
Due to the emergency nature of these studies, the consent process needs to be carefully designed,
accounting for the legal representative signing consent initially and then re-consenting once the patient is
stable and determined to be in a position to consent.
The caregiver support is imperative as most of the procedures and decisions will have to be made by this
person/legal rep due to the severity of illness.

4. When diffusion-weighted imaging (DWI) volume is used as an entry criterion this should be accounted
for planning the study and projecting enrollment: The AIS patients with DWI greater than 70 cm3
are
also at risk of post-ischemic edema, during the 72 hours post-stroke onset that could require intervention
to prevent further neurological deterioration. Furthermore, the first 24 hours could easily be spent in the
emergency room waiting for availability in the stroke unit or in transit to an institution with a critical
care stroke unit. With the short-consenting window for AIS with entry point of a few days after onset
of event, clinical teams may only have 24 hours to determine which clinical studies are suitable for the
stroke patient, since the first 72 hours may be needed to determine the maximal infarct volume.
During this first 72-hour window, the total infarct volume may still be expanding, impacting neuro-
cognitive functions in addition to motor disabilities that contribute to long-term disability. This 72-hour
window is seen as the “crisis phase” from the perspective of the patient, family or caregiver; a time when
emotions are high and patient outcomes still not clear. Neither the patient nor the patient’s family nor
caregivers are necessarily in a frame of mind to provide thoughtful insight into consenting to a clinical
study. Consideration for this clinical study should be given around consent during this “crisis phase”.
Clinical investigational sites have the challenge of assuring that the patient and/or the patient’s family,
caregiver or legal representative in the case of an enacted power of attorney are able to meet the essential
elements of informed consent. To establish the elements of informed consent, the treating physicians
may need to consult with the patient, the patient’s family or caregiver about the potential course of SOC
treatment or intervention and potential clinical studies, very early on and repeatedly during the “crisis
phase.” A skilled team at the investigational site is needed for patient and caregiver education along with
supportive educational materials explaining SOC treatments and interventions for stroke patients and
clinical studies in general.
Relationships with Regional Stroke Associations
The sponsor’s direct engagement with local professional stroke associations could be essential for the
success of a trial. In our recent experience it played an extremely positive role and some of the countries
typically without highly enrolled trials performed extremely well.
1. GBD 2016 Lifetime Risk of Stroke Collaborators. Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990–2016.
N Engl J Med. 19 Dec 2018. http://www.healthdata.org/infographic/lifetime-stroke-risk-2016
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