BASICS Trial Protocol Amendment#3 version 3.0

BASICS Trial Protocol ID/NL33550.100.10 version 3.0 02-02-2015

BASICS Trial

Basilar Artery International Cooperation Study

Research Protocol


BASICS Trial protocol

Protocol ID NL33550.100.10 / 2010B151 NHS

Short title BASICS Trial

Version 3.0

Date 02-02-2015

Coordinating investigator/project

leader

E.J.R.J. der Hoeven, MD

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


Koekoekslaan 1

3435CM Nieuwegein

The Netherlands

+31 (0) 88 - 320 30 00

[email protected]

J.A. Vos, MD, PhD, Radiology PI


Koekoekslaan 1

3435CM Nieuwegein

The Netherlands

+31 (0) 88 - 320 30 00

[email protected]


Multicenter research: per site

The Netherlands:

St. Antonius Hospital

University Medical Centre Utrecht

MC Haaglanden

St. Elisabeth Hospital Tilburg

Rijnstate Hospital Arnhem

Maastricht University Medical Center

Academic Medical Center Amsterdam

Leiden University Medical Center

University Medical Center Groningen

Haga Hospital The Hague

Switzerland:

CHUV Lausanne

Italy :

University of Modena and Reggio Emilia

Roma Umberto I Hospital

Varese Hospital

Genua Hospital

Bergamo Hospital

Czech republic:

Olomouc Hospital

Norway:

University Hospital North Norway Malmø

St Olavs Hospital Trondheim

Germany:

Dresden University Medical Center

Berlin Charité

W.J. Schonewille

L.J. Kappelle

J. Boiten

P. de Kort

J. Hofmeijer

J. Staals

P. Nederkoorn

M. Wermer

M. Uyttenboogaart

K. de Laat

P. Michel

A. Zini

M. De Michele

M.L. Delodovici

L. Malfatto

B.Censori

R. Herzig

S.H. Johnsen

G. Rohweder

V. Puetz

H. Audebert


Mannheim University Medical Center

Ravensburg

K. Szabo

C. Rueckert

Sponsor (in Dutch:

verrichter/opdrachtgever)

BASICS Study Group

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


PROTOCOL SIGNATURE SHEET

Name Signature Date

For non-commercial research,

Head of Department:

H. Koers

Coordinating Investigator:

E.J.R.J. van der Hoeven, MD



Principal Investigator:

W. J. Schonewille, MD




TABLE OF CONTENTS

1 INTRODUCTION AND RATIONALE ................................................................................10 1.1 Introduction.................................................................................................................10 1.2 Rationale ....................................................................................................................11

2. OBJECTIVES ..................................................................................................................13 3. STUDY DESIGN..............................................................................................................13 4. STUDY POPULATION ....................................................................................................14

4.1 Population (base) .......................................................................................................14 4.2 Inclusion criteria .........................................................................................................15 4.3 Exclusion criteria ........................................................................................................15 4.4 Sample size calculation..............................................................................................15

5. TREATMENT OF SUBJECTS .........................................................................................16 5.1 Investigational product/treatment ...............................................................................16

6. INVESTIGATIONAL MEDICINAL PRODUCT .................................................................16 6.1 Name and description of investigational medicinal product(s) ...................................16 6.2 Summary of findings from non-clinical studies ...........................................................17 6.3 Summary of findings from clinical studies ..................................................................17 6.4 Summary of known and potential risks and benefits ..................................................17 6.5 Description and justification of route of administration and dosage ...........................17 6.6 Dosages, dosage modifications and method of administration ..................................17 6.7 Preparation and labelling of Investigational Medicinal Product ..................................17 6.8 Drug accountability .....................................................................................................17

7. METHODS.......................................................................................................................17 7.1 Study parameters/endpoints ......................................................................................17

7.1.1 Main study parameter/endpoint............................................................................17 7.1.2 Secondary study parameters/endpoints...............................................................18 7.1.3 Other study parameters .......................................................................................18

7.2 Randomisation, blinding and treatment allocation......................................................18 7.3 Study procedures .......................................................................................................19 7.4 Withdrawal of individual subjects ...............................................................................21 7.5 Replacement of individual subjects after withdrawal. .................................................21 7.6 Follow-up of subjects withdrawn from treatment ........................................................21 7.7 Premature termination of the study ............................................................................21

8. SAFETY REPORTING ....................................................................................................21 8.1 Section 10 WMO event ..............................................................................................21 8.2 Adverse and serious adverse events .........................................................................21

8.2.1 Suspected unexpected serious adverse reactions (SUSAR)...............................22 8.2.2 Annual safety report .............................................................................................23

8.3 Follow-up of adverse events ......................................................................................23 8.4 Data Safety Monitoring Board (DSMB) ......................................................................23

9. STATISTICAL ANALYSIS ...............................................................................................24 9.1 Descriptive statistics...................................................................................................24 9.2 Univariate analysis .....................................................................................................24


9.3 Multivariate analysis ...................................................................................................24 9.4 Interim analysis ..........................................................................................................24

10. ETHICAL CONSIDERATIONS ......................................................................................25 10.1 Regulation statement................................................................................................25 10.2 Recruitment and consent..........................................................................................25 10.3 Benefits and risks assessment .................................................................................26 10.4 Compensation for injury............................................................................................26

11. ADMINISTRATIVE ASPECTS AND PUBLICATION .....................................................27 11.1 Handling and storage of data and documents..........................................................27 11.2 Amendments ............................................................................................................27 11.3 Annual progress report .............................................................................................27 11.4 End of study report ...................................................................................................28 11.5 Public disclosure and publication policy ...................................................................28

12. REFERENCES ..............................................................................................................29 13. APPENDIX 1. Allowed IA strategies. .............................................................................30


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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 Medisch-

wetenschappelijk 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 IAT in addition to best medical management

(BMM) in patients with basilar artery occlusion.

Study design: Randomised, multi-centre, open label, controlled phase III, treatment trial.

Study population: Patients, aged 18 or older, with CTA or MRA confirmed basilar occlusion.

Intervention: Patients will be randomised between BMM with additional IAT versus BMM

alone. IAT has to be initiated within 6 hours from estimated time of BAO. If treated with IVT

as part of BMM, IVT should be started within 4.5 hours of estimated time of BAO.

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 IAT 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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1 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.

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.


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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 IMS III

study used 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.

Best medical management

Best medical management consists of the standard of care of patients with acute

ischemic stroke according to existing local protocols and guidelines, and may include IV

thrombolysis.

The use of a BMM 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.


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The non-intervention hospitals are encouraged to start IVT, unless contra-indicated,

without delay before sending the patient with the clinical diagnosis of BAO to the

intervention center, where the patient will be randomized if eligible.

Additional IA treatment:

A combined BMM 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.

IAT in patients with a contra-indication for IVT seems effective in patients with anterior

circulation stroke (ref MR CLEAN). There is no data on safety or efficacy of IAT in

patients with basilar artery occlusion and a contra-indication for IVT.

• Time to treatment: based on the results of the PROACT studies the 6 hours time

window for IAT 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 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 additional

IAT arm depending on local approval and experience. Prior approval by the

steering committee needs to be obtained.


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2. OBJECTIVES

Primary Objective:

• To evaluate the efficacy of IAT in addition to BMM compared 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.

- Patients treated with IVT and those with a contra-indication for IVT.

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 modified Rankin score of 0-3, in patients

with an acute ischemic stroke caused by basilar artery occlusion.

• 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 to 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 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 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

• Patients will be randomised to combined BMM/IA versus BMM alone in a 1:1 ratio.


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• In each group the randomization will be stratified for center, NIHSS and treatment

with IVT.

• 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 BMM alone.

• Unless contra-indicated, subjects are treated with IVT 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,

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 randomised to the combined BMM/IA approach, IA therapy should be initiated

within 6 hours after estimated time of BAO.

• Needle-to-groin time for IAT is considered as initiation of therapy.

• Treatment options allowed in the additional IAT group are listed in Appendix 1 and

depend on local approval, after approval by the steering committee.

• Follow-up of patients will subsequently be performed at 24 hours ± 6 hours, 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 unless clinically contra-indicated.

• 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 or older and a documented basilar artery occlusion will be included in

the trial.


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4.2 Inclusion criteria

• Symptoms and signs compatible with ischemia in the basilar artery territory.

• Basilar artery occlusion confirmed by CTA or MRA.

• Age18 or older (i.e., candidates must have had their 18th birthday).

• If IVT is considered as part of BMM, IVT has to be initiated within 4.5 hours of

estimated time of basilar artery occlusion.

• Initiation of IA therapy should be feasible within 6 hours of estimated time of BAO.

4.3 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 favorable outcome at 90 days by additional

IA therapy by comparison with BMM, 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 BMM group. This latter

incidence was based on data of the BASICS registry study. 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.


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5. TREATMENT OF SUBJECTS

One of the guiding principles of the BASICS trial is rapid initiation of 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.

5.1 Investigational product/treatment


Unless contra-indicated patients are treated with a standard full dose of open-label IV rt-

PA (0.9mg/kg; 90mg maximum). IVT has to be initiated within 4.5 hours of estimated time

of basilar artery occlusion.

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 are listed in

Appendix 1. Choice of therapy depends on local approval and experience. 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.

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

for the principle of “time is brain”. 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.

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.


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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 BMM 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




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.

6.8 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.


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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 of randomization, at 24 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 with an imaging proven basilar artery occlusion can be considered for

enrollment in the study. Randomization follows the confirmation of basilar artery occlusion

as soon as possible by a secure link to a central randomization database.

The randomization and study enrollment process may not interfere in any way with

the timely initiation of standard IVT.

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.


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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 randomized

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 who are not randomized, 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 will be used to

identify patients eligible for the trial.

After obtained informed consent patients will be randomized 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 randomization

Patients will need a NCCT or MRI scan of the brain to exclude haemorrhage or extensive

brainstem ischemia.

All patients should have a CTA or MRA 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.

Patients transferred from community hospitals

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


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Unless clinically contra-indicated 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


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 BAO 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 BAO. 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 are listed in Appendix 1. 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 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


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Follow-up of patients will subsequently be performed at 24 hours ± 6 hours, 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

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


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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

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.


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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.

8.3 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


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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-to-

treat 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].

9.4 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


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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.

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.


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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




strokes, while maintaining a similar safety profile. The MERCI trials have shown the

safety of mechanical thrombectomy after full dose IVT.

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.


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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, 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.

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.


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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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12. REFERENCES

1. Leys, D. Atherothrombosis: a major health burden. Cerebrovasc. Dis. 2001;11 suppl

2:1-4. 2. Schonewille, WJ et al. Treatment and outcomes of acute basilar artery occlusion in

the Basilar Artery International Cooperation Study (BASICS): a prospective registry. 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. JAMA. 1999 Dec 1;282(21):2003-11.

4. Tissue plasminogen activator for acute ischemic stroke: The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Eng J Med. 1995 Dec 14;333(24):1581-7.

5. Hacke, W et al. Randomised double-blind placebo-controlled trial of thromblolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998 Oct 17;252(9136):1245-51.

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 6;363(9411):768-74.

7. Ogawa, A et al. Randomised trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke. 2007 Oct;38(10):2633-9.

8. Hacke, W et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13)1317-29.

9. Weimar, C et al. Distribution and outcome of symptomatic stenoses and occlusions in patients with acute cerebral ischemia. Arch Neurol. 2006 Sep;63(9):1287-91.

10. Lindsberg, PJ et al. Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment. Neurology. 2006 Jul 25;67(2):334-6.

11. Macleod, MR et al. Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation ischaemic stroke. Cerebrovasc Dis. 2005;20(1):12-7.

12. Lindsberg, PJ et al. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke. 2006 Mar;37(3):922-8.

13. Lewandowski, CA et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999 Dec;30(12):2598-605.

14. IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004 Apr;35(4):904-1.

15. IMS II Trial investigators. The interventional Management of Stroke (IMS) II study. Stroke 2007 Jul;38(7):2127-35.

16. Lindsberg, PJ et al. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA. 2004 Oct 20;292(15):1862-6.

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 with basilar artery occlusion. Am J Neuroradiol. 2009 Nov;30(10):1877-83.

19. Nagel, S et al. Therapy of acute basilar artery occlusion: intraarterial thrombolysis alone vs bridging therapy. Stroke. 2009 Jan;40(1):140-6.

20. Smith, WS et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008 Apr;39(4):1205-12.


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13. APPENDIX 1. Allowed IA strategies.

The following endovascular devices and treatment options (or a combination) are currently allowed for use in the intra-arterial treatment arm of the BASICS trial. - Standard microcatheter - DAC aspiration catheter - Merci (Concentric Medical) - Solitaire (Covidien) - EKOS - Trevo Pro retrievel systems (Concentric Medical) - Penumbra System - Penumbra Separator 3D - pREset Thrombectomy Retriever - Stenting - IA thrombolysis with rt-PA - IA thrombolysis with urokinase (not allowed in Germany)

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BASICS Trial Protocol Amendment#3 version 3.0

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