Basilar Artery International Cooperation Study Trial

Background
Recently our study group reported the results of the Basilar Artery
International Cooperation Study (BASICS), a prospective registry of patients
with an acute symptomatic basilar artery occlusion (BAO). The purpose of the
registry was to obtain a better understanding of outcomes following acute BAO
and to study potential differences in treatment response in anticipation of a
definitive randomised controlled acute treatment trial in these patients. We
were not able to identify a statistically significant superior treatment
strategy. However, by including more than 600 patients in the registry over a 5
years period, we did show that the performance of a randomised trial in
patients with basilar artery occlusion is feasible.

Rationale
Our observations in the BASICS registry underscore that we continue to lack a
proven treatment modality for patients with an acute BAO and that current
clinical practice varies widely. Furthermore, the often-held assumption that
IAT is superior to IVT (as part of best medical management) in patients with an
acute symptomatic BAO is challenged by our data. Although recanalization rates
after IAT have been reported to be higher in observational studies, this was
not accompanied by improved outcome.
The BASICS registry was observational and has all the limitations of a
non-randomised study.

Reasons for clinicians to select a specific treatment option are more complex
than can be captured in the scope of a prospective registry. Multivariable
analyses can never adjust completely for systematic differences between
treatment groups * the aim of randomisation in clinical trials. A bias towards
a more aggressive treatment approach in patients who were thought to have a
worse prognosis may have influenced the outcome in the IAT group and
relinquishing both IVT and IAT in patients with a severe deficit may have been
an expression of a more palliative approach. Crossover to another treatment
group because of clinical worsening or lack of treatment response was not taken
into account. There may be variables relevant to outcome that are imbalanced
between groups, but that we did not measure. However, the registry collected
standard neurological and functional scores and risk factor data across all
sites. In the analyses we have adjusted for baseline imbalances between the
treatment groups as much as possible.

As the IA treatment approach becomes increasingly available and utilized
throughout the world, we believe that a large randomised controlled phase III
trial investigating the added value of this therapy in patients with an acute
symptomatic BAO is a high priority.

Primary objective
* To evaluate the efficacy of IAT in addition to BMM compaed to BMM alone in
terms of favourable outcome at 90 days, defined as a modified Rankin score of
0-3, in patients with an acute ischemic stroke caused by basilar artery
occlusion
* Secondary analysis will compare outcome in the following pre-defined
subgroups:
- patients with a baseline NIHSS of <10, 10 -19, and those with a baseline
NIHSS of * 20.
- patients treated with IVT within 4.5 hours of symptom onset, and those
treated beyond 4.5 hours of symptom onset within 4.5 hours of estimated time of
basilar artery occlusion.

Secondary objectives
* To evaluate the efficacy of IAT in patients with a contra indication for IVT
in terms of favourable outcome at 90 days, defined as a mRS of 0-3 in patients
with an acute ischemic stroke caused by a BAO.
* To evaluate the safety of a combined IV/IA approach compared to IV rt-PA
alone. The primary measures of safety will be symptomatic intracranial
haemorrhage or intracranial haemorrhage contributing to patients death as
determined by the study safety committee confirmed on neuroimaging within 3
days of treatment initiation (CT or MRI), or overall mortality at 90 days.
* To evaluate the efficacy of IAT in addition to BMM compared with BMM alone in
terms of a favourable outcome at day 90 on other clinical and radiological
measures: 1) Excellent outcome defined as a mRS of 0-2, 2) mRS - not
dichotomized, 3) NIHSS, and EuroQol. 4) an improved early response to treatment
as determined by a reduction in NIHSS by 5 points or more at 24 hours. 5) A CT
or MR angiography assessment of basilar artery patency at 24 hours. 6) the
volume of cerebral infarction as measured on NCCT/CTA-SI at 24 hours.
* To evaluate the safety and efficacy of mechanical devices as the BASICS trial
progresses.

* Multinational, multi-centre, randomised, open-label, controlled.
* Study duration per subject will be 12 months from the time of randomisation
* Two-arm study (1:1 randomisation) comparing a combined BMM/IA approach versus
BMM alone.
* The trial is designed to test the hypothesis that there is an overall
absolute difference of 10% in favorable outcome (moderate or no disability as
measured by a modified Rankin Score of 0-3) for subjects treated with the
combined BMM/IA approach as compared to those treated with standard IV rt-PA.
* All subjects are treated with IV rt-PA as soon as possible, if eligible for
IVT. Consideration for trial participation or actual randomisation in the trial
may not cause any delay in the initiation of IV rt-PA.
* A diagnostic neuroimaging screening with CT/CTA or MRI/MRA confirming the
presence of basilar artery occlusion and the abcence of imaging exclusion
criteria will be used to identify patients eligible for the trial.
* After eligibility is confirmed and informed consent obtained from the subject
or his proxy, the subject will be randomised to additional IAT as soon as
possible.
* If IV rt-PA is given as part of BMM, IVT has to be initiated within 4.5 hours
of estimated time of occlusion. If randomised to the combined BMM/IA approach,
IA therapy should be initiated within 6 hours of estimated time of basilar
artery occlusion.
* Bolus injection in case of IV rt-PA and needle-to-groin time for IAT are
considered as initiation of therapy.
* Treatment options allowed in the IA arm include; Urokinase (max. dose
1.500.000 Units), rt-PA (max. dose 22mg), MERCI, Penumbra, EKOS, Trevo, pREset,
DAC, angioplasty and stenting, or any other thrombolitic or device depending on
local approval, after approval by the steering committee.
* Follow-up of patients will subsequently be performed at 24 hours ± 6 hours, 7
days or discharge, 3 months (blinded examiner) and at 12 months (telephone
survey).
* All patients will have a follow-up CT/CTA or MRI/MRA within 24 hours, ± 6
hours, of initiation of treatment to monitor vessel patency and presence of
intracranial haemorrhage.
* The study will have a steering committee, an independent data and safety
monitoring committee.

Treatment
One of the guiding principles of the BASICS trial is rapid initiation of
thrombolytic therapy to an eligible subject to provide maximal benefit. To
minimize any delay in the administration of a proven effective therapy (i.e.,
IV rt-PA), the standard dose of open-label IV rt-PA (0.9 mg/kg; 90 mg maximum)
is initiated prior to enrollment and randomization in the trial if standard
eligibility criteria are met.

Treatment arms
BMM
All patients are treated with a standard full dose of open-label IV rt-PA
(0.9mg/kg; 90mg maximum) if standard eligibility criteria are met. In patients
treated with IVT before estimated time of BAO a second treatment with IVT may
be considered. Patients treated with IVT within 4.5 hours of symptom onset, and
those who are treated beyond 4.5 hours of symptom onset but within 4.5 hours of
estimated time of basilar artery occlusion will be regarded as two
pre-specified subgroups for secondary analysis. In patients treated beyond 4.5
hours of symptom onset, informed consent needs to be obtained prior to
initiation of IVT.

IA therapy
IA therapy has to be initiated within 6 hours of estimated time of basilar
artery occlusion. If an appropriate thrombus or residual stenosis is
identified, the choice of IA strategy will be made by the treating
neurointerventionalist. IA treatment options available will be any of the
following devices or thrombolitics, depending on local approval and experience;
the Concentric Merci® thrombus-removal device, Penumbra, Solitaire, Trevo,
pREset, DAC, infusion of rt-PA combined with an application of low-intensity
ultrasound at the site of the occlusion via the EKOS® Micro-Infusion Catheter,
infusion of alteplase or urokinase via a standard micro-catheter.
The use of any other treatment strategy depends on local approval and
experience, and is only allowed after prior approval of the steering committee.

The IA approach is aimed at recanalization of the basilar artery. In order to
ensure optimal perfusion the aiming is that at least one posterior cerebral
artery should be patent. In the presence of residual occlusions of branches of
the basilar artery after complete recanalization of the basilar artery the use
of additional thrombolitic therapy should be kept to a minimum due to the
limited potential gain.

Clinical improvement could be a reason not to initiate IA therapy despite the
presence of persistent basilar artery occlusion on conventional angiography.
The initiation of IA therapy after identification of an appropriate thrombus in
the basilar artery or high grade
residual stenosis considered to have been the cause of occlusion on
conventional angiography will be left to the judgment of the treating
physician.

Informed consent.
-no extra burden

Intervention when randomized to IA group: arterial catheterization in the
groin, IA treatment with thrombolytic and/or device. X-rays during procedure
+possible control: max 20mSv.
- IA therapy: known risks of intraarterial treatment like intracranial
haemorrhage and catherization-complications like aneurysm spurium or haematoma
arising at the puncture site.
- Duration: 1-2 hours.
- ionising radiation: extra risk of 0.01% on fatal tumor induction (1Sv=5%).

24 hours exam: NIHSS, CT, CTA
- no extra burden, standard procedure.

1 month telephone survey: mRankin score.
- 5 minutes.

3 months blinded exam: mRS, EuroQol.
- 15 minutes.

12 month telephone survey: EuroQol, mRS.
- 10 minutes.