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BASICS Trial Protocol ID/NL33550.100.10
version 2.0 14-01-2012
BASICS Trial
Basilar Artery International Cooperation Study
Research Protocol
BASICS Trial Protocol ID/NL33550.100.10
version 2.0 14-01-2012
BASICS Trial protocol
Protocol ID
NL33550.100.10 / 2010B151 NHS
Short title
BASICS Trial
Version
2.0
Date
14-01-2012
Coordinating investigator/project
E.J.R.J. der Hoeven, MD
leader
St. Antonius Hospital, Nieuwegein
Koekoekslaan 1
3435 CM Nieuwegein
The Netherlands
+31 (0) 88 - 320 30 00
[email protected]
Principal investigator(s) (in
Dutch:
hoofdonderzoeker/uitvoerder)
W.J. Schonewille, MD, Neurology PI
St. Antonius Hospital, Nieuwegein
Koekoekslaan 1
3435CM Nieuwegein
The Netherlands
+31 (0) 88 - 320 30 00
[email protected]
J.A. Vos, MD, PhD, Radiology PI
St. Antonius Hospital, Nieuwegein
Koekoekslaan 1
3435CM Nieuwegein
The Netherlands
+31 (0) 88 - 320 30 00
[email protected]
BASICS Trial Protocol ID/NL33550.100.10
version 2.0 14-01-2012
Multicenter research: per site
St. Antonius Hospital
W.J. Schonewille. MD
Department of Neurology
St. Antonius Hospital, Nieuwegein
Koekoekslaan 1
3435CM Nieuwegein
The Netherlands
[email protected]
University Medical Centre
Utrecht
Prof. L.J. Kappelle, MD, PhD
Department of Neurology
University Medical Centre Utrecht
Heidelberglaan 100
3584CX Utrecht
The Netherlands
[email protected]
Centre Hospitalier Universitaire
Vaudois, Lausanne University
P. Michel, PD, MER, Médicin adjoint
Department of Neurlogy
University Medical Centre Vaudois
Rue du Bugnon 21
CH-1011 Lausanne
Suisse
[email protected]
Sponsor (in Dutch:
verrichter/opdrachtgever)
BASICS Study Group
BASICS Trial Protocol ID/NL33550.100.10
Independent physician(s)
P.J.A.M. Brouwers, MD, PhD
Medisch Spectrum Twente
Department of Neurology
Postbus 50.000
7500KA Enschede
The Netherlands
+31 (0) 53 - 487 28 50
version 2.0 14-01-2012
BASICS Trial Protocol ID/NL33550.100.10
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PROTOCOL SIGNATURE SHEET
Name
For non-commercial research,
Head of Department:
H. Koers
Coordinating Investigator:
E.J.R.J. van der Hoeven, MD
St. Antonius Hospital, Nieuwegein
University Medical Centre Utrecht
Principal Investigator:
W. J. Schonewille, MD
St. Antonius Hospital, Nieuwegein
University Medical Centre Utrecht
Signature
Date
BASICS Trial Protocol ID/NL33550.100.10
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TABLE OF CONTENTS
1.
1. INTRODUCTION AND RATIONALE ..........................................................................10
1.1 Introduction ................................................................................................................10
1.2 Rationale....................................................................................................................11
2. OBJECTIVES ..................................................................................................................13
3. STUDY DESIGN..............................................................................................................14
4. STUDY POPULATION ....................................................................................................15
4.1 Population (base) ......................................................................................................15
4.2 Inclusion criteria .........................................................................................................15
4.3 Exclusion criteria........................................................................................................16
4.4 Sample size calculation .............................................................................................16
5. TREATMENT OF SUBJECTS.........................................................................................16
5.1 Investigational product/treatment...............................................................................17
6. INVESTIGATIONAL MEDICINAL PRODUCT .................................................................17
6.1 Name and description of investigational medicinal product(s)...................................18
6.2 Summary of findings from non-clinical studies...........................................................18
6.3 Summary of findings from clinical studies..................................................................18
6.4 Summary of known and potential risks and benefits..................................................18
6.5 Description and justification of route of administration and dosage...........................18
6.6 Dosages, dosage modifications and method of administration .................................18
6.7 Preparation and labelling of Investigational Medicinal Product .................................18
6.8 Drug accountability ....................................................................................................19
7. METHODS.......................................................................................................................19
7.1 Study parameters/endpoints ......................................................................................19
7.1.1 Main study parameter/endpoint...........................................................................19
7.1.2 Secondary study parameters/endpoints..............................................................19
7.1.3 Other study parameters.......................................................................................19
7.2 Randomisation, blinding and treatment allocation .....................................................19
7.3 Study procedures.......................................................................................................20
7.4 Withdrawal of individual subjects ...............................................................................22
7.5 Replacement of individual subjects after withdrawal. ................................................22
7.6 Follow-up of subjects withdrawn from treatment........................................................22
7.7 Premature termination of the study............................................................................22
8. SAFETY REPORTING ....................................................................................................22
8.1 Section 10 WMO event ..............................................................................................22
8.2 Adverse and serious adverse events.........................................................................23
8.2.1 Suspected unexpected serious adverse reactions (SUSAR) ..............................23
8.2.2 Annual safety report ............................................................................................24
8.3 Follow-up of adverse events ......................................................................................25
8.4 Data Safety Monitoring Board (DSMB) ......................................................................25
9. STATISTICAL ANALYSIS ...............................................................................................25
9.1 Descriptive statistics ..................................................................................................25
9.2 Univariate analysis.....................................................................................................25
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9.3 Multivariate analysis...................................................................................................25
9.4 Interim analysis ..........................................................................................................26
10. ETHICAL CONSIDERATIONS ......................................................................................27
10.1 Regulation statement ...............................................................................................27
10.2 Recruitment and consent .........................................................................................27
10.3 Benefits and risks assessment ................................................................................27
10.4 Compensation for injury ...........................................................................................28
11. ADMINISTRATIVE ASPECTS AND PUBLICATION .....................................................28
11.1 Handling and storage of data and documents .........................................................28
11.2 Amendments............................................................................................................29
11.3 Annual progress report ............................................................................................29
11.4 End of study report...................................................................................................29
11.5 Public disclosure and publication policy...................................................................29
12. REFERENCES ..............................................................................................................30
BASICS Trial Protocol ID/NL33550.100.10
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS
ABR
ABR form, General Assessment and Registration form, is the application
form that is required for submission to the accredited Ethics Committee (In
Dutch, ABR = Algemene Beoordeling en Registratie)
AE
Adverse Event
AR
Adverse Reaction
CA
Competent Authority
CCMO
Central Committee on Research Involving Human Subjects; in Dutch:
Centrale Commissie Mensgebonden Onderzoek
CV
Curriculum Vitae
DSMB
Data Safety Monitoring Board
EU
European Union
EudraCT
European drug regulatory affairs Clinical Trials
GCP
Good Clinical Practice
IB
Investigator’s Brochure
IC
Informed Consent
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
METC
Medical research ethics committee (MREC); in Dutch: medisch ethische
toetsing commissie (METC)
(S)AE
(Serious) Adverse Event
SPC
Summary of Product Characteristics (in Dutch: officiële productinfomatie
IB1-tekst)
Sponsor
The sponsor is the party that commissions the organisation or performance
of the research, for example a pharmaceutical company, academic hospital,
scientific organisation or investigator. A party that provides funding for a
study but does not commission it is not regarded as the sponsor, but
referred to as a subsidising party.
SUSAR
Suspected Unexpected Serious Adverse Reaction
Wbp
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)
WMO
Medical Research Involving Human Subjects Act (in Dutch: Wet Medischwetenschappelijk Onderzoek met Mensen
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SUMMARY
Rationale: 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. 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 intra-arterial
therapy (IAT) is superior to intravenous thrombolysis (IVT) in patients with an acute
symptomatic BAO is challenged by our data.
The BASICS registry was observational and has all the limitations of a non-randomised
study. Interpretation of results is hampered by the lack of a standard treatment protocol for all
patients who entered the study.
Objective: Evaluate the efficacy and safety of additional IA therapy after IV thrombolysis in
patients with basilar artery occlusion.
Study design: Randomised, multi-centre, open label, controlled phase III, treatment trial.
Study population: Patients, aged 18 through 85 years, with CTA or MRA confirmed basilar
occlusion treated with IVT.
Intervention: Patients will be randomised between additional IAT followed by maximum
supportive care versus maximum supportive care alone.
IVT has to be initiated within 4.5 hours from estimated time of basilar artery occlusion and
IAT within 6 hours.
Main study parameters/endpoints: Favourable outcome at day 90 defined as a modified
Rankin Score (mRS – functional scale) of 0-3.
Nature and extent of the burden and risks associated with participation, benefit and
group relatedness: Although, to date, no data from a randomised controlled trial support the
use of IAT for BAO, IAT was by far the most commonly used treatment type in the BASICS
registry. The use of additional IAT after standard IVT is supported by the results of trials
performed with patients with occlusions in other vascular territories. Patients randomised into
the additional IAT group will undergo intra-arterial catheterization and IAT will be initiated if
indicated. Effective amount of radiation during this 1-2 hour procedure will be about 20 mSv.
Main risks for catheterization and IAT comprise local and intracranial haemorrhage. In the
BASICS registry we reported a risk for symptomatic intracranial haemorrhage of 14% in
patients treated with IAT versus 6% in patients treated with IVT. Follow-up telephone surveys
at 1 and 12 months and blinded exam at 3 months will take up to 50 minutes in total.
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INTRODUCTION AND RATIONALE
1.1
Introduction
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.
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 in patients with
an acute symptomatic BAO is challenged by our data. Although recanalization rates after
IAT are consistently higher after IAT as compared to IVT 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.
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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.
1.2
Rationale
Study population: basilar artery occlusion
There are several factors that distinguish patients with BAO from those with middle
cerebral artery (MCA) occlusion and which may warrant a different treatment approach:
•
Severity of deficit: previous studies have suggested a greater benefit of IA therapy in
patients with a severe deficit.
•
High poor outcome rate: because of a higher poor outcome rate, patients with basilar
artery occlusion have more to gain.
•
Collateral flow: the basilar artery not only receives collateral flow through cortical
cerebellar branches, comparable to the cortical hemispheric branches of the MCA,
but also by retrograde filling by the anterior circulation through the posterior
communicating arteries as part of the circle of Willis. IVT may be more effective in the
presence of good collateral flow, by attacking the thrombus from both sides.
•
Time window for treatment: the BASICS registry data suggests the presence of a
longer time window from symptom onset to time of treatment. The PROACT studies
used a limit of time from symptom onset to time of treatment of 6 hours. The current
IMS III study uses a 5 hours time window from symptom onset to initiation of IAT. The
BASICS trial uses a 6 hours time window from estimated time of basilar artery
occlusion to initiation of IA treatment. The BASICS registry used the estimated time of
symptom onset consistent with the clinical diagnosis of BAO to treatment rather than
the more commonly used time of onset of any symptoms to treatment in our
analyses.
Previous studies have shown that BAO is preceded by prodromal symptoms in over 60%
of patients. Most of these patients would be excluded from a potential trial using the time
of onset of any symptom to treatment as an inclusion criterion. We believe that our results
support the use of the estimated time of BAO rather than using the time of onset of any
symptom to treatment as an inclusion criterion for the BASICS trial.
IVT versus IVT&IAT comparison
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IV thrombolysis is the current standard of care in patients presenting with acute ischemic
stroke with a proven safety and efficacy and therefore should be regarded as the current
“Golden Standard” with which potential new treatment strategies should be compared.
The use of an IVT only arm in a trial of patients with acute symptomatic basilar artery
occlusion is supported by the results of the BASICS registry in which no significant
difference was found between IVT or IAT treated patients with a severe deficit.
The performance of a trial comparing IVT alone vs. IAT alone in patients with BAO does
not seem feasible. Referral of a patient to an intervention center in order to being
randomised between IVT vs. IAT alone would mean delaying the initiation of a treatment,
which is of proven benefit – while there is convincing evidence for the principle of “time is
brain”. The number of patients with BAO presenting directly to an intervention centre will
be too limited. Patients with basilar artery occlusion only represent an approximate 5% of
all IVT eligible patients, while only 40% of patients in the BASICS registry where admitted
directly (without referral) to an intervention center.
In order to include a sufficient number of patients the BASICS trial will therefore mainly
depend on the inclusion of patients referred from non-intervention community hospitals.
The non-intervention hospitals are encouraged to start IVT without delay before sending
the patient with the clinical diagnosis of BAO to the intervention center, where the patient
will be randomised if eligible.
A combined IV and IA approach to acute ischemic stroke therapy was designed to offer
rapid initiation of IV rt-PA, followed by additional titrated local IA therapy, to patients with
moderate-to-severe strokes (NIHSS≥10). The goal was to achieve higher rates of early,
successful reperfusion in a widely accessible manner. This approach has been
tested in clinical trials of over 200 patients, starting with the Emergency Management of
Stroke (EMS) pilot trial from 1994 to 1995, followed by the Interventional Management of
Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional
cohorts. The data from EMS and IMS show that the combined approach to recanalization
may be more effective than standard IV rt-PA alone for moderate-to-severe (NIHSS ≥10)
strokes, while maintaining a similar safety profile.
IVT arm
•
4.5 hours time window: based on the results of the ECASS III study a time window
of 0 to 4.5 hours from symptom onset to treatment in patients with acute ischemic
stroke is widely accepted. The BASICS registry results show the safety of using a
0 to 4.5 hours time window from estimated time of occlusion to treatment in
patients with acute BAO.
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Full dose IVT: in a case series of 69 patients treated with IA thrombolysis
(urokinase or alteplase) following full dose IVT symptomatic haemorrhage
occurred in 4 out of 69 (5.8%) patients. The MERCI trials have shown the safety
of mechanical thrombectomy after full dose IVT.
IAT arm
•
Time to treatment: based on the results of the PROACT studies the 6 hours time
window for IA thrombolysis in patients with MCA occlusion is widely accepted. The
MERCI studies have shown the safety of mechanical thrombectomy up to 8 hours
from symptom onset. The BASICS study shows that a time window of 0 to 6 hours
from estimated time of occlusion to IA treatment is safe in patients with a severe
deficit while little can be gained in both IVT and IAT treated patients beyond the 6
hours time window.
•
Full option IA therapy arm: the main theoretical advantage of an IA approach is
the variety of treatment options, which can be tailored to the individual patient.
Because of the great variety in IA treatment options and the limited number of
patients, the experience with specific devices or thrombolytics varies considerably
among stroke centers both within and between countries. Limiting the use of
treatment options would exclude centers from participation because of lack of
experience with the selected device or thrombolytic despite ample experience in
the use of alternative devices or thrombolytics. New devices or thrombolytics that
become available during the duration of the study may be used in the IAT arm
depending on local approval and experience. Prior approval by the steering
committee needs to be obtained.
2. OBJECTIVES
Primary Objective:
•
To evaluate the efficacy of additional IA therapy after IVT 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 -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:
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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 a combined IV/IA approach compared to IV rt-PA 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 and 3)
EQ-5D. 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
by a NCCT + CTA-SI at 24 hours.
•
To evaluate the safety and efficacy of mechanical devices as part of a combined IV/IA
approach as the BASICS trial progresses.
3. STUDY DESIGN
•
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 IV/IA approach versus IV
rt-PA 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 IV/IA approach as
compared to those treated with standard IV rt-PA.
•
All subjects are treated with IV rt-PA as soon as possible. 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 absence of imaging exclusion criteria,
and an NIHSS of 10 or more at time of randomisation 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.
•
IV rt-PA has to be initiated within 4.5 hours of estimated time of occlusion. If
randomised to the combined IV/IA approach, IA therapy should be initiated within 6
hours of estimated time of basilar artery occlusion.
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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, Solitaire, angioplasty and
stenting, or any other thrombolytic 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, 1 month (telephone survey), 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, presence of intracranial
haemorrhage and extend of ischemic changes.
•
The study will have a steering committee, an independent data and safety monitoring
committee.
4. STUDY POPULATION
4.1
Population (base)
Patients with basilar artery occlusion represent an approximate 5% of all IVT eligible
patients. By including more than 600 patients in the BASICS registry over a 5 years
period, we showed that the performance of a randomised trial comprehending 750
patients with a basilar artery occlusion is feasible.
Patients aged 18 through 85 years, treated with IVT and a documented basilar artery
occlusion will be included in the trial.
4.2
•
Inclusion criteria
Symptoms and signs compatible with ischemia in the basilar artery territory and an
NIHSS ≥ 10 at time of randomization.
•
Basilar artery occlusion confirmed by CTA or MRA.
•
Age18 through 85 years (i.e., candidates must have had their 18th birthday, but not
had their 86th birthday).
•
Initiation of IV rt-PA within 4.5 hours of estimated time of basilar artery occlusion.
(Estimated time of basilar artery occlusion is defined as time of onset of acute
symptoms leading to clinical diagnosis of basilar artery occlusion or if not known last
time patient was seen normal prior to onset of these symptoms).
•
Initiation of IA therapy should be feasible within 6 hours of estimated time of basilar
artery occlusion.
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Exclusion criteria
•
Pre-existing dependency with mRankin ≥3.
•
Females of childbearing potential who are known to be pregnant and/or lactating or
who have positive pregnancy tests on admission.
•
Patients who require hemodialysis or peritoneal dialysis.
•
Other serious, advanced, or terminal illness.
•
Any other condition that the investigator feels would pose a significant hazard to the
patient if IA therapy is initiated.
•
Current participation in another research drug treatment protocol (patient cannot start
another experimental agent until after 90 days).
•
Informed consent is not or cannot be obtained.
Imaging Exclusion Criteria
•
Lesion consistent with hemorrhage of any degree.
•
Significant cerebellar mass effect or acute hydrocephalus.
•
Bilateral extended brainstem ischemia.
4.4
Sample size calculation
Assuming an absolute risk increase of 10% of favourable outcome at 90 days by
additional IA therapy by comparison with maximum supportive care alone, we calculated
that 712 patients would be needed. This calculation was based on a type 1 error of 5%, a
type 2 error of 20%, and a presumed incidence of the primary outcome event of 30% in
the maximum supportive care group. This latter incidence was based on data of the
BASICS registry study. [ref 2 section K4] Based on these assumptions the trial would
yield a risk ratio of 1.33 with a 95% confidence interval of 1.09 to 1.63, i.e. a relative risk
increase of 33% more patients with a favorable outcome with additional IA therapy. The
sample size formula used originated from the standard work on clinical trials “Clinical
Trials: A Practical Approach” by S.J. Pocock (p 125). To account for potential dropout a
target of 750 patients is set.
5. TREATMENT OF SUBJECTS
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 openlabel 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.
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Investigational product/treatment
IV rt-PA
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. 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 prespecified 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 thrombolytics, depending on local approval and experience;
the Concentric Merci® thrombus-removal device, Penumbra, Solitaire, 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. If IA thrombolysis is the chosen strategy, a maximum of 22 mg of IA rt-PA
or 1.500.000 Units of Urokinase may be given. Stenting is allowed in the presence of a
high-grade vertebral artery stenosis or occlusion hampering adequate endovascular
access to the basilar artery and in case of a residual high-grade basilar artery stenosis.
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 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 thrombolytic 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.
6. INVESTIGATIONAL MEDICINAL PRODUCT
IV thrombolysis is the current standard of care in patients presenting with acute ischemic
stroke with a proven safety and efficacy and therefore should be regarded as the current
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for the principle of “time is brain”. All patients are treated with a standard full dose of openlabel IV rt-PA (0.9mg/kg; 90mg maximum) if standard eligibility criteria are met.
6.1
•
Name and description of investigational medicinal product(s)
Registration name: Medacinase, active substance: Urokinase, RVG 11731, powder
for solution for injection and infusion.
•
Registration name: Actilyse, active substance: Alteplase, RVG 15228, powder for
solution for injection and infusion.
6.2
Summary of findings from non-clinical studies
•
Ad I. SPC section 5 page 6.
•
Ad II. SPC section 5 page 11-13.
6.3
Summary of findings from clinical studies
•
Ad I. SPC section 5 page 6, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19
•
Ad II. SPC section 5 page 11-13, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19
6.4
Summary of known and potential risks and benefits
•
Ad I. SPC section 4 page 1-6, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19
•
Ad II. SPC section 4 page 3-11, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19
6.5
Description and justification of route of administration and dosage
A combined IV and IA approach to acute ischemic stroke therapy was designed to offer
rapid initiation of IV rt-PA, followed by additional titrated local IA therapy, to patients with
moderate-to-severe strokes (NIHSS≥10). The goal was to achieve higher rates of early,
successful reperfusion in a widely accessible manner. This approach has been
tested in clinical trials of over 200 patients, starting with the Emergency Management of
Stroke (EMS) pilot trial from 1994 to 1995, followed by the Interventional Management of
Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional
cohorts. The data from EMS and IMS show that the combined approach to recanalization
may be more effective than standard IV rt-PA alone for moderate-to-severe (NIHSS ≥10)
strokes, while maintaining a similar safety profile. The MERCI trials have shown the
safety of mechanical thrombectomy after full dose IVT.
6.6
Dosages, dosage modifications and method of administration
•
Ad I. Maximum of 1.500.000 Units intra-arterial.
•
Ad II. Maximum of 22 mg intra-arterial.
6.7
Preparation and labelling of Investigational Medicinal Product
Medacinase and Actilyse are commercially available products.
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Drug accountability
Medacinase and Actilyse are commercially available products.
7. METHODS
7.1
Study parameters/endpoints
7.1.1 Main study parameter/endpoint
Favourable outcome at day 90 defined as a modified Rankin Score (mRS –
functional scale) of 0-3.
7.1.2 Secondary study parameters/endpoints
Excellent outcome at day 90 defined as a modified Rankin Score (mRS – functional
scale) of 0-2.
Modified Rankin Score – not dichotomized.
National Institutes of Health Stroke Scale (NIHSS – acute assessment scale) at time
of IVT, at time randomization, at 48 hours post treatment.
EQ-5D (quality of life) at day 90 and at 12 months
7.1.3
Other study parameters
Radiologic outcomes
Recanalization at 24 hours, ± 6 hours, by CT angiography.
Volume of cerebral infarction on NCCT and CTA source images.
Safety outcomes
Symptomatic intracranial hemorrhage at 24 hours CT imaging, ± 6 hours.
Mortality at 90 days.
Quality of life outcomes
EuroQol EQ-5D
7.2
Randomisation, blinding and treatment allocation
Study enrollment
Only subjects treated with IVT within 4.5 hours of estimated time of basilar artery
occlusion can be considered for enrollment in the study. Randomization follows the
confirmation of basilar artery occlusion as soon as possible.
Patients are randomised by a secure link to a central randomization database.
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The randomization and study enrollment process may not interfere in any way with
the timely initiation of standard IVT.
Subjects treated with standard IVT who did not fulfill all inclusion/exclusion criteria at the
time of IVT may not be considered for randomization.
Based on the experience in the BASICS registry an estimated 40 to 50% of patients will
present in community hospitals with subsequent referral to an intervention center.
Community hospitals should be encouraged to initiate IVT prior to transfer according to
the “drip and ship” principle. Intubation prior to transfer should be strongly encouraged in
any subject deemed unstable or at high risk of aspiration. If sedation is needed, short
acting drugs, like propofol (di-isopropylfenol) should be given to avoid interference with
the neurological examination upon arrival at the intervention center. In case of an
increase in NIHSS by ≥ 5 points during transfer and in any comatose subject a repeat CT
scan of the brain should be performed prior to randomization.
Utmost care is taken to avoid unnecessary delay between IVT and the initiation of IAT.
Registry of patients with basilar artery occlusion who are not randomised
To evaluate a possible selection bias of patients included in the trial, participating centers
are obliged to enter all trial eligible patients with acute symptomatic basilar artery
occlusion presenting at their center which are not randomised, in a registry. Data are
collected on baseline characteristics, reason for non-inclusion and type of treatment.
7.3
Study procedures
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.
A diagnostic neuroimaging screening with CT/CTA or ,MRI/MRA confirming the presence
of basilar artery occlusion and the absence of imaging exclusion criteria, and an NIHSS of
10 or more will be used to identify patients eligible for the trial.
After obtained informed consent patients will be randomised in one of two treatment
arms.
Imaging
CT is the preferred imaging modality. MRI may be used if part of the local standard
imaging protocol.
Prior to IVT
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Patients will need a NCCT or MRI scan of the brain prior to initiation of IVT to exclude
hemorrhage or extensive brainstem ischemia.
Prior to randomization
All patients should have a CTA or MRA before, during or at the end of IVT and prior to
randomization, for confirmation of BAO. Confirmation of BAO should not delay the
initiation of IVT. IVT should preferably be started immediately following NCCT/MRI, prior
to CTA/MRA.
Repeat CTA or MRA before randomization is not mandatory, but recommended in case of
significant neurological improvement or worsening, and in case of a more than 2 hours
time delay after initial confirmation of BAO.
24 hours follow-up
All patients will have a follow-up CT/CTA or MRI/MRA within 24hours ± 6 hours of
initiation of treatment to monitor vessel patency, presence of intracranial haemorrhage
and extend of ischemic changes.
Treatment arms
IV rt-PA
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. 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 prespecified 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 thrombolytics, depending on local approval and experience;
the Concentric Merci® thrombus-removal device, Penumbra, Solitaire, 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. If IA thrombolysis is the chosen strategy, a maximum of 22 mg of IA rt-PA
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or 1.500.000 Units of Urokinase may be given. Stenting is allowed in the presence of a
high-grade vertebral artery stenosis or occlusion hampering adequate endovascular
access to the basilar artery and in case of a residual high grade basilar artery stenosis.
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 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 thrombolytic 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.
Follow-up
Follow-up of patients will subsequently be performed at 24 hours ± 6 hours, 7 days or
discharge, 1 month (telephone survey: mRS) 3 months (blinded examiner mRS, EQ-5D)
and at 12 months (telephone survey: EQ-5D, mRS).
7.4
Withdrawal of individual subjects
Subjects can leave the study at any time for any reason if they wish to do so without any
consequences. The investigator can decide to withdraw a subject from the study for
urgent medical reasons.
7.5
Replacement of individual subjects after withdrawal.
After withdrawal from the study individuals will not be replaced.
7.6
Follow-up of subjects withdrawn from treatment
Subjects withdrawn from treatment will be followed-up if informed consent is maintained.
7.7 Premature termination of the study
For procedures concerning premature termination of the study we refer to chapter 9.4.
8. SAFETY REPORTING
8.1
Section 10 WMO event
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the
subjects and the reviewing accredited METC if anything occurs, on the basis of which it
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appears that the disadvantages of participation may be significantly greater than was
foreseen in the research proposal. The study will be suspended pending further review by
the accredited METC, except insofar as suspension would jeopardise the subjects’
health. The investigator will take care that all subjects are kept informed.
8.2
Adverse and serious adverse events
Adverse events are defined as any undesirable experience occurring to a subject during
the study, whether or not considered related to the investigational product or the
experimental treatment. All adverse events reported spontaneously by the subject or
observed by the investigator or his staff will be recorded.
A serious adverse event is any untoward medical occurrence or effect that at any dose:
-
results in death;
-
is life threatening (at the time of the event);
-
requires prolongation of existing inpatients’ hospitalisation;
-
results in persistent or significant disability or incapacity;
-
is a new event of the trial likely to affect the safety of the subjects, such as an
unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the
treatment of a life threatening disease, major safety finding from a newly completed
animal study, etc.
Acute basilar artery occlusion has a high morbidity and mortality. All deaths and
adverse events will be collected and analysed by an independent AE-committee. An
independent medical monitor will direct this committee. When they conclude that the
event is attributable to the treatment and is not a result of the disease, the event will
be reported as a SAE. All SAEs will be reported through the web portal
ToetsingOnline to the accredited METC that approved the protocol, within 15 days
after the sponsor has first knowledge of the serious adverse reactions.
SAEs that result in death or are life threatening should be reported expedited. The
expedited reporting will occur not later than 7 days after the responsible investigator
has first knowledge of the adverse reaction. This is for a preliminary report with
another 8 days for completion of the report.
8.2.1 Suspected unexpected serious adverse reactions (SUSAR)
Adverse reactions are all untoward and unintended responses to the investigational
product related to any dose administered.
Unexpected adverse reactions are adverse reactions, of which the nature, or
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severity, is not consistent with the applicable product information (Summary of
Product Characteristics (SPC)).
The sponsor will report expedited the following SUSARs through the web portal
ToetsingOnline to the METC:
−
SUSARs that have arisen in the clinical trial that was assessed by the METC;
−
SUSARs that have arisen in other clinical trials of the same sponsor and with the
same medicinal product, and that could have consequences for the safety of the
subjects involved in the clinical trial that was assessed by the METC.
The remaining SUSARs are recorded in an overview list (line-listing) that will be
submitted once every half year to the METC. This line-listing provides an overview
of all SUSARs from the study medicine, accompanied by a brief report highlighting
the main points of concern.
The expedited reporting of SUSARs through the web portal ToetsingOnline is
sufficient as notification to the competent authority.
The sponsor will report expedited all SUSARs to the competent authorities in other
Member States, according to the requirements of the Member States.
The expedited reporting will occur not later than 15 days after the sponsor has first
knowledge of the adverse reactions. For fatal or life threatening cases the term will
be maximal 7 days for a preliminary report with another 8 days for completion of the
report.
8.2.2 Annual safety report
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a
year throughout the clinical trial, a safety report to the accredited METC, competent
authority, Medicine Evaluation Board and competent authorities of the concerned
Member States.
This safety report consists of:
−
a list of all suspected (unexpected or expected) serious adverse reactions, along
with an aggregated summary table of all reported serious adverse reactions,
ordered by organ system, per study;
−
a report concerning the safety of the subjects, consisting of a complete safety
analysis and an evaluation of the balance between the efficacy and the
harmfulness of the medicine under investigation.
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Follow-up of adverse events
All adverse events will be followed until they have abated, or until a stable situation has
been reached. Depending on the event, follow up may require additional tests or medical
procedures as indicated, and/or referral to the general physician or a medical specialist.
8.4
Data Safety Monitoring Board (DSMB)
An independent Data Safety and Monitoring Board, consisting of clinicians familiar with
the treatment of stroke, a biostatistician and a neuro-interventionalist, will be established
to monitor the progress of the trial. Additionally, two stroke neurologists will be appointed
as internal and external safety monitors. The Internal Safety Monitor will review safety
data on an ongoing basis, including monitoring the trend in serious adverse outcome
events and submitting reports to regulatory agencies. The External Safety Monitor, an
independent and experienced neurologist, will review all serious life-threatening bleeding
events during this study and be the final adjudicator of intracranial hemorrhage endpoints
(symptomatic or asymptomatic and the relationship to study intervention) when there is
disagreement between the local site and the Internal Medical Monitor. This is the same
methodology used by the NINDS rt-PA Stroke Trial and IMS Studies. Details on the
advice(s) of the DSMB will be notified upon receipt by the sponsor to the METC that
approved the protocol. With this notification a statement will be included indicating
whether the advice will be followed.
9. STATISTICAL ANALYSIS
9.1
Descriptive statistics
Continuous data will be summarised with means and standard deviations. For count data
percentages will be given.
9.2
Univariate analysis
The primary aim of the analysis is to compare the proportion of patients with a favourable
outcome at 90 days between the two treatment groups. For this purpose a risk ratio with
corresponding 95% CI will be calculated. The analyses will be based on the intention-totreat principle.
9.3
Multivariate analysis
Multivariable analyses will only be carried out if important incomparability is detected
between the two treatment groups. In that case risk ratios will be calculated that are
adjusted for the variables that show baseline imbalance. To this end Poisson regression
will be used, similar to that used in the BASICS registry study [ref 2 chapter 12].
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Interim analysis
An independent data safety monitoring board will monitor the trial. For efficacy a
symmetrical two-sided stopping rule will be used. The size of the trial is based on the
assumption of a 10% absolute increase of the proportion of patients with a favorable
outcome treated with additional IA therapy as compared with maximum supportive care
alone. If the observed benefit is ‘clearly’ larger or if maximum supportive treatment
appears to be better than additional IA therapy early termination of the trial may be
recommended. A restricted procedure (Whitehead1997; PEST 4) will be used with alpha
equal to 0.05 and a power of 0.80.
Safety will be monitored as follows. The BASICS registry observed that the risk of
symptomatic intracranial hemorrhage in patients treated with IA therapy was 14% (95%
CI 10-18%) and 7% (95%CI 3-11%) in those treated with IVT only. [ref Lancet Neurology
2009] A more than two-fold excess of symptomatic intracranial hemorrhage in the group
treated with additional IA therapy as compared with maximum supportive treatment may
therefore be considered as problematic. However, symptomatic intracranial hemorrhage
is a contributing component of the primary outcome and hence is weighed during
monitoring of this outcome. Nevertheless the Steering Committee of the BASICS trial will
develop a criterion in close collaboration with the DSMB of the trial when an excess of
symptomatic intracranial hemorrhage would warrant at least reconsideration of
continuation of the trial.
The BASICS Trial Office will put an active follow-up system into effect, such that for each
patient 90-day follow-up data and those on the occurrence of symptomatic intracranial
hemorrhage are obtained without delay. After the collection of the follow-up data on ten
patients and after each safety outcome these data will be sent to the DSMB that will
perform an interim analysis. Every four months the DSMB will advise the steering
committee about the continuation of the trial. The recommendation on the continuation
will be based on 1) stopping rules as described above and 2) the most recent information
from medical literature or congresses in the field of cerebrovascular disease.
References
Whitehead J. The design and analysis of sequential clinical trials. rev. 2nd ed. 1997, John
Wiley & Sons, Chichester.
PEST 4: Operating Manual. MPS Research Unit (2000). The University of Reading.
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10. ETHICAL CONSIDERATIONS
10.1 Regulation statement
The study will be conducted according to the principles of the Declaration of Helsinki
(www.wma.net 21-10-2008) and in accordance with the Medical Research Involving
Human Subjects Act (WMO).
10.2 Recruitment and consent
See also chapter 7.2.
The responsible neurologist or neurology resident obtains informed consent. In acute
situations or if the patient is incapable to give written informed consent oral informed
consent may be obtained. In case of oral informed consent a witness (e.g. family or
nurse) should be present when the information is presented to the patient or patient
representative. A written summary that describes the essential information will be
presented to the patient or patient representative. The witness, and responsible
neurologist or neurology resident will sign this short document.
In case of a comatose subject informed consent can be obtained from the patient’s proxy
in person or by telephone as long as the identity of the proxy can be confirmed.
Community hospitals are encouraged to obtain informed preliminary consent for trial
participation of the subject or his proxy prior to transfer.
In patients who are not eligible for standard IVT because IVT cannot be initiated within
4.5 hours of symptom onset, who can be treated within 4.5 hours of estimated time of
BAO informed consent has to be obtained prior to IVT. In those centers where CTA or
MRA is not part of the standard acute stroke work-up informed consent has to be
obtained prior to CTA or MRA.
10.3 Benefits and risks assessment
A combined IV and IA approach to acute ischemic stroke therapy was designed to offer
rapid initiation of IV rt-PA, followed by additional titrated local IA therapy, to patients with
moderate-to-severe strokes (NIHSS≥10). The goal was to achieve higher rates of early,
successful reperfusion in a widely accessible manner. This approach has been tested in
clinical trials of over 200 patients, starting with the Emergency Management of Stroke
(EMS) pilot trial from 1994 to 1995, followed by the Interventional Management of
Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional
cohorts. The data from EMS and IMS show that the combined approach to recanalization
may be more effective than standard IV rt-PA alone for moderate-to-severe (NIHSS ≥10)
strokes, while maintaining a similar safety profile. The MERCI trials have shown the
safety of mechanical thrombectomy after full dose IVT.
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10.4 Compensation for injury
The sponsor/investigator has a liability insurance which is in accordance with article 7,
subsection 6 of the WMO.
The sponsor (also) has an insurance which is in accordance with the legal requirements
in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for
Clinical Research in Humans of 23th June 2003). This insurance provides cover for
damage to research subjects through injury or death caused by the study.
1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each
subject who participates in the Research;
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for
all subjects who participate in the Research;
3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the
organisation for all damage disclosed by scientific research for the Sponsor as
‘verrichter’ in the meaning of said Act in each year of insurance coverage.
The insurance applies to the damage that becomes apparent during the study or within 4
years after the end of the study.
11. ADMINISTRATIVE ASPECTS AND PUBLICATION
11.1 Handling and storage of data and documents
After randomization all patient data (including digital case record forms) will be kept in a
Data management system. The principal investigator safeguards the key to the code.
All de-identified imaging data will be sent to the Clinical Coordinating Center at the St.
Antonius Hospital, Nieuwegein for standardized CD archiving and data blinding (if
needed). CT and CTA imaging will then be transferred to the Imaging Analysis Center at
the University of Dresden for central interpretation by a blinded three-member consensus
panel. To expedite safety reporting, all acute CT data received from a clinical center will
initially be reviewed by a blinded central reader at the St. Antonius Hospital, Nieuwegein.
All angiographic data will be reviewed by two independent readers at the Angiographic
Imaging Center at the University of Bern, and a third reader will provide final adjudication
as needed.
The handling of all personal data will comply with the Dutch Personal Data Protection Act.
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11.2 Amendments
A ‘substantial amendment’ is defined as an amendment to the terms of the METC
application, or to the protocol or any other supporting documentation, that is likely to
affect to a significant degree:
- the safety or physical or mental integrity of the subjects of the trial;
- the scientific value of the trial;
- the conduct or management of the trial; or
- the quality or safety of any intervention used in the trial.
All substantial amendments will be notified to the METC and to the competent authority.
Non-substantial amendments will not be notified to the accredited METC and the
competent authority, but will be recorded and filed by the sponsor.
11.3 Annual progress report
The sponsor/investigator will submit a summary of the progress of the trial to the
accredited METC once a year. Information will be provided on the date of inclusion of the
first subject, numbers of subjects included and numbers of subjects that have completed
the trial, serious adverse events/ serious adverse reactions, other problems, and
amendments.
11.4 End of study report
The sponsor will notify the accredited METC and the competent authority of the end of
the study within a period of 90 days. The end of the study is defined as the last patient’s
last visit.
In case the study is ended prematurely, the sponsor will notify the accredited METC and
the competent authority within 15 days, including the reasons for the premature
termination.
Within one year after the end of the study, the investigator/sponsor will submit a final
study report with the results of the study, including any publications/abstracts of the study,
to the accredited METC and the Competent Authority.
11.5 Public disclosure and publication policy
Publication policy is in accordance with the CCMO’s statement containing the basic
principles of the CCMO’s position on the disclosure/publication of research results
obtained from studies involving human subjects. Results will be disclosed unreservedly.
The BASICS trial will be registered in a public trial registry.
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2. Schonewille, WJ et al. Treatment and outcomes of acute basilar artery occlusion in
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Lancet Neurol. 2009 Aug;8(8):724-30.
3. Furlan, A et al. Intra-arterial prourokinase for acute ischemic stroke: the PROACT II
study: a randomised controlled trial. Prolyse in Acute Cerebral Thromboembolism.
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6. Hacke, W et al. Association of outcome with early stroke treatment: pooled analysis
of ATLANTIS, ECASS and NINDS rt-PA stroke trials. Lancet. 2004 Mar
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intervention trial (MELT) Japan. Stroke. 2007 Oct;38(10):2633-9.
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9. Weimar, C et al. Distribution and outcome of symptomatic stenoses and occlusions in
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10. Lindsberg, PJ et al. Door to thrombolysis: ER reorganization and reduced delays to
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11. Macleod, MR et al. Results of a multicentre, randomised controlled trial of intraarterial urokinase in the treatment of acute posterior circulation ischaemic stroke.
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17. Pfefferkorn, T et al. Drip, ship, and retrieve: cooperative recanalization therapy in
acute basilar artery occlusion. Stroke. 2010 Apr;41(4):722-6.
18. Puetz, V et al. CT angiography source images predict final infarct extent in patients
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19. Nagel, S et al. Therapy of acute basilar artery occlusion: intraarterial thrombolysis
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