Berkhemer PDF
Berkhemer PDF
Berkhemer PDF
original article
A BS T R AC T
Background
In patients with acute ischemic stroke caused by a proximal intracranial arterial The authors’ full names, academic de-
occlusion, intraarterial treatment is highly effective for emergency revasculariza- grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
tion. However, proof of a beneficial effect on functional outcome is lacking. Dippel at the Department of Neurology
Methods H643, Erasmus MC University Medical
Center, PO Box 2040, Rotterdam 3000
We randomly assigned eligible patients to either intraarterial treatment plus usual CA, the Netherlands, or at d.dippel@
care or usual care alone. Eligible patients had a proximal arterial occlusion in the erasmusmc.nl.
anterior cerebral circulation that was confirmed on vessel imaging and that could
Drs. Berkhemer, Fransen, and Beumer and
be treated intraarterially within 6 hours after symptom onset. The primary out- Drs. van Zwam, Roos, van der Lugt, van
come was the modified Rankin scale score at 90 days; this categorical scale mea- Oostenbrugge, Majoie, and Dippel con-
sures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). tributed equally to this article.
The treatment effect was estimated with ordinal logistic regression as a common *A complete list of investigators in the
odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds Multicenter Randomized Clinical Trial
ratio measured the likelihood that intraarterial treatment would lead to lower mod- of Endovascular Treatment for Acute
Ischemic Stroke in the Netherlands
ified Rankin scores, as compared with usual care alone (shift analysis). (MR CLEAN) is provided in the Supple-
Results mentary Appendix, available at NEJM.org.
We enrolled 500 patients at 16 medical centers in the Netherlands (233 assigned to in- This article was published on December
traarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 17, 2014, at NEJM.org.
23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before ran- DOI: 10.1056/NEJMoa1411587
domization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to Copyright © 2014 Massachusetts Medical Society.
intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence
interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points
(95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score,
0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differ-
ences in mortality or the occurrence of symptomatic intracerebral hemorrhage.
Conclusions
In patients with acute ischemic stroke caused by a proximal intracranial occlusion
of the anterior circulation, intraarterial treatment administered within 6 hours af-
ter stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and
others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current
Controlled Trials number, ISRCTN10888758.)
n engl j med nejm.org 1
The New England Journal of Medicine
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Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
I
ntravenous alteplase administered Me thods
within 4.5 hours after symptom onset is the
only reperfusion therapy with proven efficacy Study Design
in patients with acute ischemic stroke.1 However, MR CLEAN was a pragmatic, phase 3, multicenter
well-recognized limitations of this therapy in- clinical trial with randomized treatment-group
clude the narrow therapeutic time window and assignments, open-label treatment, and blinded
contraindications such as recent surgery, coagu- end-point evaluation. Intraarterial treatment (in-
lation abnormalities, and a history of intracrani- traarterial thrombolysis, mechanical treatment,
A Quick Take
al hemorrhage.2 Moreover, intravenous alteplase or both) plus usual care (which could include in-
is available at
NEJM.org appears to be much less effective at opening travenous administration of alteplase) was com-
proximal occlusions of the major intracranial ar- pared with usual care alone (control group) in pa-
teries, which account for more than one third of tients with acute ischemic stroke and a proximal
cases of acute anterior-circulation stroke.3,4 Early intracranial arterial occlusion of the anterior cir-
recanalization after intravenous alteplase is seen culation that was confirmed on vessel imaging.
in only about one third of patients with an occlu- The study protocol (available with the full text
sion of the internal-carotid-artery terminus,5 and of this article at NEJM.org) was approved by a cen-
the prognosis without revascularization is gener- tral medical ethics committee and the research
ally poor for such patients.6 For these reasons, board of each participating center. All patients or
intraarterial treatment is regarded as a poten- their legal representatives provided written in-
tially important component of the therapeutic formed consent before randomization.
armamentarium. Members of the executive committee and the
Intraarterial therapy can be broadly divided local investigators designed the study, collected
into chemical dissolution of clots with locally and analyzed the data, wrote the manuscript,
delivered thrombolytic agents and clot retrieval and made the decision to submit the manuscript
or thrombectomy with mechanical devices. Al- for publication. The authors vouch for the accu-
though early randomized trials and subsequent racy and completeness of the data and for the fidel-
meta-analyses7 showed a benefit of treatment with ity of this report to the study protocol. The study
prourokinase8,9 or urokinase,10 their results are sponsors were not involved in the study design,
not directly applicable to current decision making study conduct, protocol review, or manuscript
about treatment because the control groups did preparation or review.
not include intravenous alteplase, and mechani-
cal approaches have largely replaced locally ap- Patients and Participating Centers
plied thrombolytic agents as first-line therapy.11 The study was conducted at 16 centers in the
The neutral results of the recent randomized, Netherlands. Patients were 18 years of age or
controlled trials of intraarterial treatment have older (no upper age limit) with acute ischemic
contributed to uncertainty regarding the efficacy stroke caused by an intracranial occlusion in the
of the catheter-based approach.12-14 Numerous anterior circulation artery. Initiation of intraarte-
questions have been raised concerning the design rial treatment had to be possible within 6 hours
and conduct of these trials, including a relatively after stroke onset. Eligible patients had an occlu-
long interval before intraarterial treatment, the sion of the distal intracranial carotid artery, mid-
absence of pretreatment vascular imaging to con- dle cerebral artery (M1 or M2), or anterior cere-
firm a proximal intracranial occlusion, and the bral artery (A1 or A2), established with computed
limited use of third-generation mechanical throm- tomographic (CT) angiography (CTA), magnetic
bectomy devices such as retrievable stents. In the resonance angiography (MRA), or digital-subtrac-
Multicenter Randomized Clinical Trial of Endo- tion angiography (DSA), and a score of 2 or higher
vascular Treatment for Acute Ischemic Stroke in on the National Institutes of Health Stroke Scale
the Netherlands (MR CLEAN), we assessed wheth- (NIHSS; range, 0 to 42, with higher scores indi-
er intraarterial treatment plus usual care would cating more severe neurologic deficits). Inclusion
be more effective than usual care alone in patients of patients with an additional extracranial inter-
with a proximal arterial occlusion in the anterior nal-carotid-artery occlusion or dissection was left
cerebral circulation that could be treated intra- to the judgment of the treating physician. Detailed
arterially within 6 hours after symptom onset. inclusion and exclusion criteria are listed in the
study protocol. We did not keep a log of patients hours and the final infarct volume on noncon-
who were screened for eligibility. trast CT at 5 to 7 days.
Safety variables included hemorrhagic com-
Randomization plications, progression of ischemic stroke, new
The randomization procedure was Web-based, with ischemic stroke into a different vascular territo-
the use of permuted blocks. We stratified random- ry, and death. If neurologic deterioration devel-
ization according to medical center, use of intrave- oped, additional neuroimaging was required.
nous alteplase (yes or no), planned treatment Symptomatic intracranial hemorrhage was de-
method (mechanical or other), and stroke sever- fined as neurologic deterioration (an increase of
ity (NIHSS score of ≤14 or >14). 4 or more points in the score on the NIHSS) and
evidence of intracranial hemorrhage on imaging
Intervention studies. Local neurologists were aware of the
Intraarterial treatment consisted of arterial cath- treatment-group assignments and reported seri-
eterization with a microcatheter to the level of ous adverse events through our Web-based data-
occlusion and delivery of a thrombolytic agent, base or by fax or e-mail.
mechanical thrombectomy, or both. The method
of intraarterial treatment was left to the discre- Clinical and Radiologic Assessment
tion of the local interventionist. All patients underwent clinical assessment (in-
The use of alteplase or urokinase for intraar- cluding determination of the NIHSS score) at
terial thrombolysis was allowed in this trial, baseline, after 24 hours, and at 5 to 7 days or at
with a maximum dose of 90 mg of alteplase or discharge if earlier. A single experienced trial in-
1,200,000 IU of urokinase. The dose was re- vestigator, who was unaware of the treatment-
stricted to 30 mg of alteplase or 400,000 IU of group assignments, conducted the follow-up in-
urokinase if intravenous alteplase was given. terviews at 90 days by telephone with the patient,
Mechanical treatment could involve thrombus re- proxy, or health care provider. This interview
traction, aspiration, wire disruption, or use of a provided reports for the assessment of the modi-
retrievable stent. fied Rankin score by reviewers who remained
Only devices that had received U.S. Food and unaware of the treatment-group assignments.16-18
Drug Administration approval or a Conformité The imaging committee evaluated the find-
Européenne (CE) marking and were approved by ings on baseline noncontrast CT for the Alberta
the steering committee could be used in the Stroke Program Early Computed Tomography
trial. One or more members of each intervention Score (ASPECTS; range, 0 to 10, with 1 point
team had to have completed at least five full subtracted for any evidence of early ischemic
procedures with a particular type of device.15 change in each defined region on the CT scan),19
baseline vessel imaging (CTA, MRA, or DSA) for
Outcome and Safety Measures the location of the occlusion, and follow-up CTA
The primary outcome was the score on the mod- or MRA at 24 hours for vessel recanalization.
ified Rankin scale at 90 days. The modified Recanalization was classified as complete or not
Rankin scale is a 7-point scale ranging from 0 complete and was further evaluated with the use
(no symptoms) to 6 (death). A score of 2 or less of the modified Arterial Occlusive Lesion score
indicates functional independence.16 (see the Supplementary Appendix, available at
Secondary outcomes included the NIHSS NEJM.org, for details about scales).20,21 Follow-
score at 24 hours and at 5 to 7 days or discharge up CT scans obtained at 5 days were assessed for
if earlier, activities of daily living measured with the presence of intracranial hemorrhage.22 All
the Barthel index, and the health-related quality neuroimaging studies were evaluated by two neu-
of life measured with the EuroQol Group 5-Dimen- roradiologists who were unaware of the treat-
sion Self-Report Questionnaire at 90 days.17,18 ment-group assignments. The final infarct vol-
We examined the following prespecified dichoto- ume on the follow-up CT scan was assessed with
mizations of the modified Rankin score: 0 or 1 the use of an automated, validated algorithm.23
versus 2 to 6, 0 to 2 versus 3 to 6, and 0 to 3 versus An independent core laboratory assessed angio-
4 to 6. Imaging outcomes included arterial re- graphic outcomes on DSA imaging, using the
canalization measured with CTA or MRA at 24 modified Thrombolysis in Cerebral Infarction
(TICI) score, which ranges from 0 (no reperfu- Assuming a 10% crossover rate,26 we calcu-
sion) to 3 (complete reperfusion). 21 lated that a sample of 500 patients (250 patients
in each group) would yield a power of 82%, at a
Statistical Analysis significance level of 0.05, to detect a treatment
All analyses were based on the intention-to-treat effect that resulted in an absolute increase of 10
principle. The primary effect variable was the ad- percentage points in the proportion of patients
justed common odds ratio for a shift in the direc- with a modified Rankin score of 0 to 3 in the
tion of a better outcome on the modified Rankin intervention group as compared with the pro-
scale; this ratio was estimated with multivariable portion in the control group.
ordinal logistic regression.24 We calculated an
adjusted odds ratio for all possible cutoff values R e sult s
on the modified Rankin scale to assess the con-
sistency of effect and the plausibility of propor- Randomization and Baseline Characteristics
tionality of the odds ratio. The adjusted common Between December 2010 and March 2014, a total
odds ratio and all secondary effect variables were of 502 patients underwent randomization in 16
adjusted for potential imbalances in the follow- Dutch centers. Two patients, whose representatives
ing major prognostic variables between the inter- withdrew consent immediately after randomization
vention group and the control group: age; stroke and assignment to the control group, could not be
severity (NIHSS score) at baseline; time from included in the intention-to-treat analysis.
stroke onset to randomization; status with re- The mean age of the 500 study participants was
spect to previous stroke, atrial fibrillation, and 65 years (range, 23 to 96); 292 participants
diabetes mellitus; and occlusion of the internal- (58.4%) were men. Risk factors for a poor out-
carotid-artery terminus (yes vs. no).25 We imput- come, clinical risk factors for stroke, and aspects
ed missing values of baseline variables that were of prerandomization treatment were evenly dis-
used to adjust the regression models of treatment tributed between the two treatment groups (Table
effect on primary and secondary outcomes with 1, and Table S1 in the Supplementary Appendix).
mean or mode, as applicable. No outcomes were
imputed, except for single missing values of Treatment Assignments and Crossovers
items on the NIHSS at 24 hours and at 5 to 7 days In total, 233 patients (46.6%) were assigned to
or discharge. Patients who died were not assigned the intervention group and 267 patients (53.4%)
NIHSS scores and were not included in analyses were assigned to the control group. One patient
of such scores. received intraarterial treatment after being as-
The adjusted and unadjusted common odds ra- signed to the control group. Intraarterial treat-
tios are reported with 95% confidence intervals to ment was never initiated in 17 patients (7.3%)
indicate statistical precision. Binary outcomes were assigned to the intervention group (Fig. S1 in the
analyzed with logistic regression and are reported Supplementary Appendix).
as adjusted and unadjusted odds ratios with 95%
confidence intervals. All P values are two-sided. Intervention Details
Treatment-effect modification was explored Actual intraarterial therapy (with or without me-
in prespecified subgroups of patients, defined by chanical thrombectomy) was performed in 196 of
NIHSS score (2 to 15, 16 to 19, or ≥20), age (≥80 the 233 patients in the intervention group (84.1%).
years or <80 years), occlusion of the internal- In 88 patients (37.8%), general anesthesia was used.
carotid-artery terminus (yes or no), additional A simultaneous second revascularization proce-
extracranial internal-carotid-artery occlusion (yes dure (acute cervical carotid stenting) was per-
or no), time from stroke onset to randomization formed in 30 patients (12.9%).
(≤120 minutes or >120 minutes), and ASPECTS Mechanical treatment was performed in 195
(0 to 4, 5 to 7, or 8 to 10). The statistical sig- of the 233 patients (83.7%). Retrievable stents were
nificance of possible differences between sub- used in 190 patients (81.5%), and other devices were
groups in the treatment effect was tested with used in 5 patients (2.1%) (Table S2 in the Supple-
interaction terms. No adjustments for multiple mentary Appendix). Additional intraarterial throm-
tests were made. All analyses were performed bolytic agents were given to 24 patients (10.3%).
with the use of the Stata/SE statistical package, Intraarterial thrombolytic agents were used
version 13.1 (StataCorp). as monotherapy in 1 of the 233 patients (0.4%).
Intervention Control
Characteristic (N = 233) (N = 267)
Age — yr
Median 65.8 65.7
Interquartile range 54.5–76.0 55.5–76.4
Male sex — no. (%) 135 (57.9) 157 (58.8)
NIHSS score†
Median (interquartile range) 17 (14–21) 18 (14–22)
Range 3–30 4–38
Location of stroke in left hemisphere — no. (%) 116 (49.8) 153 (57.3)
History of ischemic stroke — no. (%) 29 (12.4) 25 (9.4)
Atrial fibrillation — no. (%) 66 (28.3) 69 (25.8)
Diabetes mellitus — no. (%) 34 (14.6) 34 (12.7)
Prestroke modified Rankin scale score — no. (%)‡
0 190 (81.5) 214 (80.1)
1 21 (9.0) 29 (10.9)
2 12 (5.2) 13 (4.9)
<2 10 (4.3) 11 (4.1)
Systolic blood pressure — mm Hg§ 146±26.0 145±24.4
Treatment with IV alteplase — no. (%) 203 (87.1) 242 (90.6)
Time from stroke onset to start of IV alteplase — min
Median 85 87
Interquartile range 67–110 65–116
ASPECTS — median (interquartile range)¶ 9 (7–10) 9 (8–10)
Intracranial arterial occlusion — no./total no. (%)‖
Intracranial ICA 1/233 (0.4) 3/266 (1.1)
ICA with involvement of the M1 middle cerebral artery segment 59/233 (25.3) 75/266 (28.2)
M1 middle cerebral artery segment 154/233 (66.1) 165/266 (62.0)
M2 middle cerebral artery segment 18/233 (7.7) 21/266 (7.9)
A1 or A2 anterior cerebral artery segment 1/233 (0.4) 2/266 (0.8)
Extracranial ICA occlusion — no./total no. (%)‖** 75/233 (32.2) 70/266 (26.3)
Time from stroke onset to randomization — min††
Median 204 196
Interquartile range 152–251 149–266
Time from stroke onset to groin puncture — min
Median 260 NA
Interquartile range 210–313
* The intervention group was assigned to intraarterial treatment plus usual care, and the control group was assigned to
usual care alone. Plus–minus values are means ±SD. ICA denotes internal carotid artery, IV intravenous, and NA not
applicable.
† Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating
more severe neurologic deficits. The NIHSS is a 15-item scale, and values for 30 of the 7500 items were missing
(0.4%). The highest number of missing items for a single patient was 6.
‡ Scores on the modified Rankin scale of functional disability range from 0 (no symptoms) to 6 (death). A score of 2 or
less indicates functional independence.
§ Data on systolic blood pressure at baseline were missing for one patient assigned to the control group.
¶ The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a measure of the extent of stroke.
Scores ranges from 0 to 10, with higher scores indicating fewer early ischemic changes. Scores were not available for
four patients assigned to the control group: noncontrast computed tomography was not performed in one patient,
and three patients had strokes in the territory of the anterior cerebral artery.
‖ Vessel imaging was not performed in one patient in the control group, so the level of occlusion was not known.
** Extracranial ICA occlusions were reported by local investigators.
†† Data were missing for two patients in the intervention group.
No intervention was given in 37 patients (15.9%) tion. The adjusted common odds ratio was 1.67
(Fig. S1 in the Supplementary Appendix). (95% confidence interval [CI], 1.21 to 2.30) (Ta-
ble 2). The shift toward better outcomes in favor
Primary Outcome of the intervention was consistent for all catego-
Data on the primary outcome (the score on the ries of the modified Rankin scale, except for
modified Rankin scale at 90 days) were com- death (Fig. 1). The absolute between-group dif-
plete. There was a shift in the distribution of the ference in the proportion of patients who were
primary-outcome scores in favor of the interven- functionally independent (modified Rankin score,
of a modified TICI score of 2a to 3 and a Throm- prognosis at baseline. The advantage is a wide
bolysis in Myocardial Ischemia score of 2 or 3, generalizability of our results.
respectively.27,28 Differentiation between a modi- Finally, although the outcome assessment was
fied TICI score of 2a and a score of 2b or 3 is blinded, patients were aware of the treatment-
difficult when lateral DSA images are not avail- group assignments, and this might have influ-
able. This applied to 15 patients in MR CLEAN, enced their opinions about their health and func-
who were subsequently given a modified TICI tional condition. However, modified Rankin scores
score of 2a. This may have led to an underesti- at 90 days were based on assessment by reviewers
mation of the actual reperfusion rate among who were unaware of the treatment-group assign-
patients with a modified TICI score of 2b or 3. ments, to avoid biased assessments, and the re-
Third, despite the positive result of this trial, sults of blinded assessments of neuroimaging
almost 9% of the patients in the intervention corroborated our findings.
group had embolization into new vascular ter- In conclusion, we found that intraarterial
ritories on DSA. A total of 30 patients (13%) treatment in patients with acute ischemic stroke
assigned to intraarterial treatment also under- caused by a proximal intracranial occlusion of
went a simultaneous second revascularization the anterior circulation was effective and safe
procedure (acute cervical carotid stenting), and when administered within 6 hours after stroke
this complexity needs to be considered when onset.
interpreting our trial results. Supported by the Dutch Heart Foundation and by unrestricted
Fourth, a relatively low proportion of patients grants from AngioCare Covidien/ev3, Medac/Lamepro, and Pen-
in the control group had a modified Rankin score umbra.
Dr. Yoo reports receiving grant support from Penumbra; Dr.
of 0 to 2 at the 90-day follow-up assessment. Brouwer, lecture fees and fees for trial management from
This may be explained by our broad inclusion Stryker, lecture fees and fees for proctoring from BALT, lecture
criteria, which allowed contraindications for fees from Toshiba, teaching fees and fees for research and devel-
opment from Codman/DePuy Synthes, and teaching fees from
intravenous alteplase, nonresponse to intravenous Sequent Medical; Dr. de Vries, consulting fees from Stryker and
alteplase, octogenarians and even nonagenarians, grant support from Covidien/ev3; and Dr. René van den Berg,
and patients with extracranial internal-carotid- consulting fees from Codman/DePuy Synthes. No other poten-
tial conflict of interest relevant to this article was reported.
artery occlusions or dissections. Taken together, Disclosure forms provided by the authors are available with
this resulted in a population with a relatively poor the full text of this article at NEJM.org.
Appendix
The authors’ full names and academic degrees are as follows: Olvert A. Berkhemer, M.D., Puck S.S. Fransen, M.D., Debbie Beumer,
M.D., Lucie A. van den Berg, M.D., Hester F. Lingsma, Ph.D., Albert J. Yoo, M.D., Wouter J. Schonewille, M.D., Jan Albert Vos, M.D.,
Ph.D., Paul J. Nederkoorn, M.D., Ph.D., Marieke J.H. Wermer, M.D., Ph.D., Marianne A.A. van Walderveen, M.D., Ph.D., Julie Staals,
M.D., Ph.D., Jeannette Hofmeijer, M.D., Ph.D., Jacques A. van Oostayen, M.D., Ph.D., Geert J. Lycklama à Nijeholt, M.D., Ph.D., Jelis
Boiten, M.D., Ph.D., Patrick A. Brouwer, M.D., Bart J. Emmer, M.D., Ph.D., Sebastiaan F. de Bruijn, M.D., Ph.D., Lukas C. van Dijk,
M.D., L. Jaap Kappelle, M.D., Ph.D., Rob H. Lo, M.D., Ewoud J. van Dijk, M.D., Ph.D., Joost de Vries, M.D., Ph.D., Paul L.M. de Kort,
M.D., Ph.D., Willem Jan J. van Rooij, M.D., Ph.D., Jan S.P. van den Berg, M.D., Ph.D., Boudewijn A.A.M. van Hasselt, M.D., Leo A.M.
Aerden, M.D., Ph.D., René J. Dallinga, M.D., Marieke C. Visser, M.D., Ph.D., Joseph C.J. Bot, M.D., Ph.D., Patrick C. Vroomen, M.D.,
Ph.D., Omid Eshghi, M.D., Tobien H.C.M.L. Schreuder, M.D., Roel J.J. Heijboer, M.D., Koos Keizer, M.D., Ph.D., Alexander V. Tiel-
beek, M.D., Ph.D., Heleen M. den Hertog, M.D., Ph.D., Dick G. Gerrits, M.D., Renske M. van den Berg-Vos, M.D., Ph.D., Giorgos B.
Karas, M.D., Ewout W. Steyerberg, M.D., Ph.D., H. Zwenneke Flach, M.D., Henk A. Marquering, Ph.D., Marieke E.S. Sprengers, M.D.,
Ph.D., Sjoerd F.M. Jenniskens, M.D., Ph.D., Ludo F.M. Beenen, M.D., René van den Berg, M.D., Ph.D., Peter J. Koudstaal, M.D., Ph.D.,
Wim H. van Zwam, M.D., Ph.D., Yvo B.W.E.M. Roos, M.D., Ph.D., Aad van der Lugt, M.D., Ph.D., Robert J. van Oostenbrugge, M.D.,
Ph.D., Charles B.L.M. Majoie, M.D., Ph.D., and Diederik W.J. Dippel, M.D., Ph.D.
The authors’ affiliations are as follows: the Departments of Radiology (O.A.B., H.A.M., M.E.S.S., L.F.M.B., R.B., C.B.L.M.M.), Neu-
rology (L.A.B., P.J.N., Y.B.W.E.M.R.), and Biomedical Engineering and Physics (H.A.M.), Academic Medical Center, the Departments
of Neurology (M.C.V.) and Radiology (J.C.J.B.), VU Medical Center, and the Departments of Neurology (R.M.B.-V.) and Radiology
(G.B.K.), Sint Lucas Andreas Hospital, Amsterdam, the Departments of Neurology (O.A.B., P.S.S.F., D.B., P.J.K., D.W.J.D.), Radiology
(P.S.S.F., P.A.B., B.J.E., A.L.), and Public Health (H.F.L., E.W.S.), Erasmus University Medical Center, Rotterdam, the Department of
Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht (D.B., J.S., R.J.O.) and the Depart-
ment of Radiology, Maastricht University Medical Center (W.H.Z.), Maastricht, the Departments of Neurology (W.J.S.) and Radiology
(J.A.V.), Sint Antonius Hospital, Nieuwegein, the Departments of Neurology (M.J.H.W.) and Radiology (M.A.A.W.), Leiden University
Medical Center, Leiden, the Departments of Neurology (J.H.) and Radiology (J.A.O.), Rijnstate Hospital, Arnhem, the Departments of
Radiology (G.J.L.N.) and Neurology (J.B.), MC Haaglanden, and the Departments of Neurology (S.F.B.) and Radiology (L.C.D.), HAGA
Hospital, The Hague, the Departments of Neurology (L.J.K.) and Radiology (R.H.L.), University Medical Center Utrecht, Utrecht, the
Departments of Neurology (E.J.D.) and Neurosurgery (J.V.), and Radiology (S.F.M.J.), Radboud University Medical Center, Nijmegen,
the Departments of Neurology (P.L.M.K.) and Radiology (W.J.J.R.), Sint Elisabeth Hospital, Tilburg, the Departments of Neurology
(J.S.P.V.) and Radiology (B.A.A.M.H., H.Z.F.), Isala Klinieken, Zwolle, the Departments of Neurology (L.A.M.A.) and Radiology (R.J.D.),
Reinier de Graaf Gasthuis, Delft, the Departments of Neurology (P.C.V.) and Radiology (O.E.), University Medical Center Groningen,
Groningen, the Departments of Neurology (T.H.C.M.L.S.) and Radiology (R.J.J.H.), Atrium Medical Center, Heerlen, the Departments
of Neurology (K.K.) and Radiology (A.V.T.), Catharina Hospital, Eindhoven, and the Departments of Neurology (H.M.H.) and Radiol-
ogy (D.G.G.), Medical Spectrum Twente, Enschede — all in the Netherlands; and the Department of Radiology, Massachusetts Gen-
eral Hospital, Boston (A.J.Y.).
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Guidelines for the early management of travenous t-PA versus t-PA alone for measurement in follow-up noncontrast
patients with acute ischemic stroke: a stroke. N Engl J Med 2013;368:893-903. CT scans of patients with acute ischemic
guideline for healthcare professionals [Erratum, N Engl J Med 2013;368:1265.] stroke. AJNR Am J Neuroradiol 2013;34:
from the American Heart Association/ 13. Ciccone A, Valvassori L, Nichelatti M, 1522-7.
American Stroke Association. Stroke et al. Endovascular treatment for acute 24. Saver JL. Novel end point analytic
2013;44:870-947. ischemic stroke. N Engl J Med 2013;368: techniques and interpreting shifts across
3. Beumer D, Saiedie G, Fonvile S, et al. 904-13. the entire range of outcome scales in
Intra-arterial occlusion in acute ischemic 14. Kidwell CS, Jahan R, Gornbein J, et al. acute stroke trials. Stroke 2007;38:3055-
stroke: relative frequency in an unselected A trial of imaging selection and endovas- 62.
population. Cerebrovasc Dis 2013;35:Suppl: cular treatment for ischemic stroke. 25. Hernández AV, Steyerberg EW,
66. N Engl J Med 2013;368:914-23. Habbema JD. Covariate adjustment in
4. Heldner MR, Zubler C, Mattle HP, et al. 15. Fransen PS, Beumer D, Berkhemer randomized controlled trials with dichot-
National Institutes of Health Stroke Scale OA, et al. MR CLEAN, a multicenter ran- omous outcomes increases statistical pow-
score and vessel occlusion in 2152 patients domized clinical trial of endovascular er and reduces sample size requirements.
with acute ischemic stroke. Stroke 2013; treatment for acute ischemic stroke in the J Clin Epidemiol 2004;57:454-60.
44:1153-7. Netherlands: study protocol for a ran- 26. Whitehead J. Sample size calculations
5. Christou I, Burgin WS, Alexandrov domized controlled trial. Trials 2014;15: for ordered categorical data. Stat Med
AV, Grotta JC. Arterial status after intrave- 343. 1993;12:2257-71. [Erratum, Stat Med 1994;
nous TPA therapy for ischaemic stroke: a 16. van Swieten JC, Koudstaal PJ, Visser 13:871.]
need for further interventions. Int Angiol MC, Schouten HJ, van Gijn J. Interob- 27. Nogueira RG, Lutsep HL, Gupta R, et
2001;20:208-13. server agreement for the assessment of al. Trevo versus Merci retrievers for throm-
6. Lima FO, Furie KL, Silva GS, et al. handicap in stroke patients. Stroke 1988; bectomy revascularisation of large vessel
Prognosis of untreated strokes due to an- 19:604-7. occlusions in acute ischaemic stroke
terior circulation proximal intracranial 17. EuroQol Group. EuroQol — a new fa- (TREVO 2): a randomised trial. Lancet
arterial occlusions detected by use of cility for the measurement of health-relat- 2012;380:1231-40. [Erratum, Lancet 2012;
computed tomography angiography. JAMA ed quality of life. Health Policy 1990;16: 380:1230.]
Neurol 2014;71:151-7. 199-208. 28. Saver JL, Jahan R, Levy EI, et al. Soli-
7. Lee M, Hong KS, Saver JL. Efficacy of 18. Mahoney FI, Barthel DW. Functional taire flow restoration device versus the
intra-arterial fibrinolysis for acute ische evaluation: the Barthel Index. Md State Merci retriever in patients with acute is
mic stroke: meta-analysis of randomized Med J 1965;14:61-5. chaemic stroke (SWIFT): a randomised,
controlled trials. Stroke 2010;41:932-7. 19. Barber PA, Demchuk AM, Zhang J, parallel-group, non-inferiority trial. Lan-
8. del Zoppo GJ, Higashida RT, Furlan AJ, Buchan AM. Validity and reliability of a cet 2012;380:1241-9.
Pessin MS, Rowley HA, Gent M. PROACT: quantitative computed tomography score 29. Dorn F, Stehle S, Lockau H, Zimmer
a phase II randomized trial of recombi- in predicting outcome of hyperacute C, Liebig T. Endovascular treatment of
nant pro-urokinase by direct arterial de- stroke before thrombolytic therapy. Lan- acute intracerebral artery occlusions with
livery in acute middle cerebral artery stroke. cet 2000;355:1670-4. [Erratum, Lancet the solitaire stent: single-centre experi-
Stroke 1998;29:4-11. 2000;355:2170.] ence with 108 recanalization procedures.
9. Furlan A, Higashida R, Wechsler L, et 20. Khatri P, Neff J, Broderick JP, Khoury Cerebrovasc Dis 2012;34:70-7.
al. Intra-arterial prourokinase for acute JC, Carrozzella J, Tomsick T. Revascular- 30. Pereira VM, Gralla J, Davalos A, et al.
ischemic stroke — the PROACT II study: a ization end points in stroke intervention- Prospective, multicenter, single-arm study
randomized controlled trial. JAMA 1999; al trials: recanalization versus reperfu- of mechanical thrombectomy using Soli-
282:2003-11. sion in IMS-I. Stroke 2005;36:2400-3. taire Flow Restoration in acute ischemic
10. Ogawa A, Mori E, Minematsu K, et al. 21. Zaidat OO, Yoo AJ, Khatri P, et al. Rec- stroke. Stroke 2013;44:2802-7.
Randomized trial of intraarterial infusion ommendations on angiographic revascu- Copyright © 2014 Massachusetts Medical Society.
of urokinase within 6 hours of middle ce- larization grading standards for acute
rebral artery stroke: the Middle Cerebral ischemic stroke: a consensus statement.
Artery Embolism Local Fibrinolytic Inter- Stroke 2013;44:2650-63.
edi t or i a l
Intravenous thrombolytic therapy is the only sible, and use modern thrombectomy devices.9
proven treatment for acute ischemic stroke, but The results of the first such trial now appear in
its use is limited by a brief time window of up to the Journal.10 The Multicenter Randomized Clini-
4.5 hours after the onset of symptoms1 and a cal Trial of Endovascular Treatment of Acute Is-
recanalization rate of less than 50%. Large clots chemic Stroke in the Netherlands (MR CLEAN)
in vessels such as the distal internal carotid ar- included patients with severe stroke and proxi-
tery or the first segment of the middle cerebral mal-vessel occlusion. Almost 90% of the pa-
artery respond poorly to intravenous thromboly- tients received intravenous thrombolysis first,
sis.2 The need for a treatment for patients who and almost all the devices used were of the
do not have a good response to intravenous retrievable-stent variety, which have a track record
treatment alone remains pressing. of successful recanalization. Thrombectomy im-
On the basis of compelling anecdotal experi- proved outcomes, with an absolute difference of
ence, stroke specialists had hoped that transvas- 13.5 percentage points in the rate of functional
cular recanalization would be an alternative to or independence, as assessed with the use of the
a follow-on treatment after intravenous therapy modified Rankin scale. Most other prespecified
for severe strokes with large-vessel occlusion. clinical end points and the rate of recanalization
However, three randomized, controlled trials of favored transvascular treatment, although the re-
intraarterial treatment, all reported in the Journal, canalization rate with transvascular treatment
have had negative or ambiguous results.3-5 These was a little lower than expected. There were no
trials were criticized for their use of older re- significant differences in mortality or the occur-
canalization devices, which were associated with rence of symptomatic intracranial hemorrhage.
lower recanalization rates than those found with Readers may wonder how the trialists from
newer devices such as retrievable stents6; for the a country with only 16.8 million inhabitants
long interval between the onset of stroke and succeeded in enrolling 500 patients in just over
intervention; and for disappointingly low recruit- 3 years, whereas other trials from much larger
ment rates, which suggested that many suitable regions with similarly advanced medical systems
patients had been treated outside the trials. struggled with recruitment. The well-established
Moreover, subgroup analyses suggested that network of investigator-initiated stroke trials in
there was a benefit for patients treated in shorter the Netherlands contributed to the success of
time windows.7,8 Perhaps most important, two the trial, as did the relatively short distances be-
of the trials did not require evidence of an oc- tween the 15 intervention centers in the coun-
cluded vessel before randomization, thereby mak- try. In my view, however, the most important
ing intracerebral treatment futile from the start. reason for success was the decision by the Dutch
The lessons of these studies were that trials government to pay for the use of thrombectomy
of intraarterial treatment should enroll patients devices only in the context of a randomized trial,
with severe strokes, have proof of proximal ves- thereby precluding treatment outside the trial.
sel occlusion, initiate treatment as early as pos- This policy may be difficult to implement in
other health systems, but imagine what prog- bolysis with alteplase for acute ischaemic stroke: a meta-analysis
of individual patient data from randomised trials. Lancet 2014
ress the medical-device field would see if this August 5 (Epub ahead of print).
strategy were the rule. 2. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R,
Finally, what does this first positive throm- Deuschl G, Jansen O. The importance of size: successful recan-
alization by intravenous thrombolysis in acute anterior stroke
bectomy trial mean for interventional treatment? depends on thrombus length. Stroke 2011;42:1775-7.
Is there any doubt left, or should thrombectomy 3. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular
now become the new standard treatment for se- therapy after intravenous t-PA versus t-PA alone for stroke. N Engl
J Med 2013;368:893-903. [Erratum, N Engl J Med 2013;368:1265.]
vere stroke with proximal large-vessel occlusion 4. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treat-
up to 6 hours after stroke onset? Several similar ment for acute ischemic stroke. N Engl J Med 2013;368:904-13.
trials are ongoing; it is premature to conclude 5. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging
selection and endovascular treatment for ischemic stroke. N Engl
that there is no longer equipoise regarding J Med 2013;368:914-23.
thrombectomy. We need and will get results 6. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration
from other well-designed trials, not only to con- device versus the Merci Retriever in patients with acute ischaemic
stroke (SWIFT): a randomised, parallel-group, non-inferiority
firm or refute the results of MR CLEAN but also trial. Lancet 2012;380:1241-9.
to look at effects in subgroups (according to 7. Khatri P, Yeatts SD, Mazighi M, et al. Time to angiographic
stroke severity, occlusion site, or time to treat- reperfusion and clinical outcome after acute ischaemic stroke:
an analysis of data from the Interventional Management of
ment initiation), for which most single trials are Stroke (IMS III) phase 3 trial. Lancet Neurol 2014;13:567-74.
underpowered. MR CLEAN is the first step in 8. Mazighi M, Chaudhry SA, Ribo M, et al. Impact of onset-to-
the right direction. reperfusion time on stroke mortality: a collaborative pooled
analysis. Circulation 2013;127:1980-5.
Disclosure forms provided by the author are available with the 9. Hacke W, Furlan AJ. (Here comes that) razors edge — endo-
full text of this article at NEJM.org. vascular stroke therapy: the end, or only the beginning? Int J
Stroke 2013;8:331-3.
From the Department of Neurology, University Hospital Heidel-
10. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized
berg, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.
trial of intraarterial treatment for acute ischemic stroke. N Engl
This article was published on December 17, 2014, at NEJM.org. J Med. DOI: 10.1056/NEJMoa1411587.
1. Emberson J, Lees KR, Lyden P, et al. Effect of treatment de- DOI: 10.1056/NEJMe1413346
lay, age, and stroke severity on the effects of intravenous throm- Copyright © 2014 Massachusetts Medical Society.
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for
acute ischemic stroke. N Engl J Med. DOI: 10.1056/NEJMoa1411587
Supplement)to)“A"randomized*trial*of!
intra#arterial!treatment'for'acute'
ischemic'stroke”!
List!of!MR!CLEAN!investigators!and!affiliations!.........................................................................!2!
Acknowledgements!...................................................................................................................!4!
Data!monitoring!and!safety!board:!.......................................................................................!4!
Advisory!board:!.....................................................................................................................!4!
Research!nurses!/!local!trial!coordinators:!............................................................................!4!
PhD!/!Medical!students:!........................................................................................................!4!
Additional!Methods!..................................................................................................................!6!
Intervention!..........................................................................................................................!6!
Clinical!&!radiological!assessment!........................................................................................!6!
Trial!organization!..................................................................................................................!6!
Supplemental!Results!and!Subgroup!analyses!..........................................................................!8!
Figure!S!1!CONSORT!flow!diagram!............................................................................................!9!
Figure!S!2!Subgroup!analyses!..................................................................................................!10!
Table!S!1!Overview!of!additional!clinical!characteristics!.........................................................!11!
Table!S!2!Number!of!patients!treated!and!treatment!details!by!center!.................................!12!
Table!S!3!Definition!and!distribution!of!modified!Arterial!Occlusive!Lesion!(mAOL)!score!....!13!
Table!S!4!Definition!and!distribution!of!mTICI!score!...............................................................!14!
Table!S!5!Breakdown!of!the!primary!outcome!and!treatment!effect!.....................................!15!
Table!S!6!Number!of!patients!with!imputed!values!................................................................!16!
! !
! 1!
List%of%MR%CLEAN%investigators%and%affiliations%%
Olvert!A.!Berkhemer,!M.D.,*,1,2!Puck!S.S.!Fransen,!M.D.,*,2,3!Debbie!Beumer,!M.D.,*2,4!Lucie!A.!
van!den!Berg,!M.D.,5!Hester!F.!Lingsma,!M.D.,!Ph.D.,7!Albert!J.!Yoo,!M.D.,8!Wouter!J.!
Schonewille,!M.D.,9!Jan!Albert!Vos,!M.D.,!Ph.D.,10!Paul!J.!Nederkoorn,!M.D.,!Ph.D.,5!Marieke!
J.H.!Wermer,!M.D.,!Ph.D.,11!Marianne!A.A.!van!Walderveen,!M.D.,!Ph.D.,12!Julie!Staals,!M.D.,!
Ph.D.,4!Jeannette!Hofmeijer,!M.D.,!Ph.D.,13!Jacques!A.!van!Oostayen,!M.D.,!Ph.D.,14!Geert!J.!
Lycklama!à!Nijeholt,!M.D.,!Ph.D.,15!Jelis!Boiten,!M.D.,!Ph.D.,16!Patrick!A.!Brouwer,!M.D.,3!Bart!
J.!Emmer,!M.D.,!Ph.D.,3!Sebastiaan!F.!de!Bruijn,!M.D.,!Ph.D.,17!Lukas!C.!van!Dijk,!M.D.,18!L.!
Jaap!Kappelle,!M.D.,!Ph.D.,19!Rob!H.!Lo,!M.D.,20!Ewoud!J.!van!Dijk,!M.D.,!Ph.D.,21!Joost!de!
Vries,!M.D.,!Ph.D.,22!Paul!L.M.!de!Kort,!M.D.,!Ph.D.,23!Willem!Jan!J.!van!Rooij,!M.D.,!Ph.D.,24!
Jan!S.P.!van!den!Berg,!M.D.,!Ph.D.,25!Boudewijn!A.A.M.!van!Hasselt,!M.D.,26!Leo!A.M.!Aerden,!
M.D.,!Ph.D.,27!René!J.!Dallinga,!M.D.,28!Marieke!C.!Visser,!M.D.,!Ph.D.,29!Joseph!C.J.!Bot,!M.D.,!
Ph.D.,30!Patrick!C.!Vroomen,!M.D.,!Ph.D.,31!Omid!Eshghi,!M.D.,!32!Tobien!H.C.M.L.!Schreuder,!
M.D.,33!Roel!J.J.!Heijboer,!M.D.,34!Koos!Keizer,!M.D.,!Ph.D.,35!Alexander!V.!Tielbeek,!M.D.,!
Ph.D.,36!Heleen!M.!den!Hertog,!M.D.,!Ph.D.,37!Dick!G.!Gerrits,!M.D.,!38!Renske!M.!van!den!
Berg#Vos,!M.D.,!Ph.D.,39!Giorgos!B.!Karas,!M.D.,40!Ewout!W.!Steyerberg,!M.D.,!Ph.D.,7!H.!
Zwenneke!Flach,!M.D.,26!Henk!A.!Marquering!Ph.D.,41,1!Marieke!E.S.!Sprengers,!M.D.,!Ph.D.,1!
Sjoerd!F.M.!Jenniskens,!M.D.,!Ph.D.,42!Ludo!F.M.!Beenen,!M.D.,1!René!van!den!Berg,!M.D.,!
Ph.D.,1!Peter!J.!Koudstaal,!M.D.,!Ph.D.,2!Wim!H.!van!Zwam,!M.D.,!Ph.D.,#,6!Yvo!B.W.E.M.!
Roos,!M.D.,!Ph.D.,!#,5!Aad!van!der!Lugt,!M.D.,!Ph.D.,!#,3!Robert!J.!van!Oostenbrugge,!M.D.,!
Ph.D.,!#,4!Charles!B.L.M.!Majoie,!M.D.,!Ph.D.,!#,1!and!Diederik!W.J.!Dippel,!M.D.,!Ph.D.!#,2!
*!Berkhemer,!Fransen!and!Beumer!contributed!equally.!
#!van!Zwam,!Roos,!van!der!Lugt,!van!Oostenbrugge,!Majoie!and!Dippel!contributed!equally.!
1!Department!of!Radiology,!Academic!Medical!Center!Amsterdam,!the!Netherlands;!2!
Department!of!Neurology,!Erasmus!MC!University!Medical!Center!Rotterdam,!the!
Netherlands;!3!Department!of!Radiology,!Erasmus!MC!University!Medical!Center!Rotterdam,!
the!Netherlands;!4!Department!of!Neurology,!Maastricht!University!Medical!Center!and!
Cardiovascular!Research!Institute!Maastricht!(CARIM),!the!Netherlands;!5!Department!of!
Neurology,!Academic!Medical!Center!Amsterdam,!the!Netherlands;!6!Department!of!
Radiology,!Maastricht!University!Medical!Center,!the!Netherlands;!7!Department!of!Public!
Health,!Erasmus!MC!University!Medical!Center!Rotterdam,!the!Netherlands;!8!Department!
of!Radiology,!Massachusetts!General!Hospital,!Boston,!United!States!of!America;!9!
! 2!
Department!of!Neurology,!Sint!Antonius!Hospital,!Nieuwegein,!the!Netherlands;!10!
Department!of!Radiology,!Sint!Antonius!Hospital,!Nieuwegein,!the!Netherlands;!11!
Department!of!Neurology,!Leiden!University!Medical!Center,!the!Netherlands;!12!
Department!of!Radiology,!Leiden!University!Medical!Center,!the!Netherlands;!13!
Department!of!Neurology,!Rijnstate!Hospital,!Arnhem,!the!Netherlands;!14!Department!of!
Radiology,!Rijnstate!Hospital,!Arnhem,!the!Netherlands;!15!Department!of!Radiology,!MC!
Haaglanden,!the!Hague,!the!Netherlands;!16!Department!of!Neurology,!MC!Haaglanden,!the!
Hague,!the!Netherlands;!17!Department!of!Neurology,!HAGA!Hospital,!the!Hague,!the!
Netherlands;!18!Department!of!Radiology,!HAGA!Hospital,!the!Hague,!the!Netherlands;!19!
Department!of!Neurology,!University!Medical!Center!Utrecht,!the!Netherlands;!20!
Department!of!Radiology,!University!Medical!Center!Utrecht,!the!Netherlands;!21!
Department!of!Neurology,!Radboud!University!Medical!Center,!Nijmegen,!the!Netherlands;!
22!Department!of!Neurosurgery,!Radboud!University!Medical!Center,!Nijmegen,!the!
Netherlands;!23!Department!of!Neurology,!Sint!Elisabeth!Hospital,!Tilburg,!the!Netherlands;!
24!Department!of!Radiology,!Sint!Elisabeth!Hospital,!Tilburg,!the!Netherlands;!25!
Department!of!Neurology,!Isala!Klinieken,!Zwolle,!the!Netherlands;!26!Department!of!
Radiology,!Isala!Klinieken,!Zwolle,!the!Netherlands;!27!Department!of!Neurology,!Reinier!de!
Graaf!Gasthuis,!Delft,!the!Netherlands;!28!Department!of!Radiology,!Reinier!de!Graaf!
Gasthuis,!Delft,!the!Netherlands;!29!Department!of!Neurology,!VU!Medical!Center,!
Amsterdam,!the!Netherlands;!30!Department!of!Radiology,!VU!Medical!Center,!Amsterdam,!
the!Netherlands;!31!Department!of!Neurology,!University!Medical!Center!Groningen,!the!
Netherlands;!32!Department!of!Radiology,!University!Medical!Center!Groningen,!the!
Netherlands;!33!Department!of!Neurology,!Atrium!Medical!Center,!Heerlen,!the!
Netherlands;!34!Department!of!Radiology,!Atrium!Medical!Center,!Heerlen,!the!Netherlands;!
35!Department!of!Neurology,!Catharina!Hospital,!Eindhoven,!the!Netherlands;!36!
Department!of!Radiology,!Catharina!Hospital,!Eindhoven,!the!Netherlands!37!Department!of!
Neurology,!Medical!Spectrum!Twente,!Enschede,!the!Netherlands;!38!Department!of!
Radiology,!Medical!Spectrum!Twente,!Enschede,!the!Netherlands;!39!Department!of!
Neurology,!Sint!Lucas!Andreas!Hospital,!Amsterdam,!the!Netherlands;!40!Department!of!
Radiology,!Sint!Lucas!Andreas!Hospital,!Amsterdam,!the!Netherlands;!41!Department!of!
Biomedical!Engineering!and!Physics,!Academic!Medical!Center!Amsterdam,!the!Netherlands;!
42!Department!of!Radiology,!Radboud!University!Medical!Center,!Nijmegen,!the!
Netherlands!
! %
! 3!
Acknowledgements%
The!MR!CLEAN!trial!was!funded!by!the!Dutch!Heart!Foundation!and!through!unrestricted!
grants!from!AngioCare!BV,!Covidien/EV3®,!MEDAC!Gmbh/LAMEPRO!and!Penumbra!Inc.!
We!thank!the!following!persons!for!their!help!and!advise!during!the!conduct!of!MR!CLEAN:!
Data%monitoring%and%safety%board:%
Chair:!Martin!M.!Brown,!National!Hospital!for!Neurology!&!Neurosurgery,!London,!
UK.!Member:!Thomas!Liebig,!Med.!Fakultät,!Univ!Köln,!Germany,!Independent!Statistician:!
Theo!Stijnen,!Leiden!University!Medical!Center,!Leiden,!the!Netherlands!
Advisory%board:%
Tommy!Andersson,!neuro!interventionist,!Karolinska!Univeristy!Hospital,!Stockholm,!
Sweden,!Heinrich!Mattle,!neurologist,!University!hospital,!Bern,!Switzerland,!Nils!Wahlgren,!
neurologist,!Karolinska!Hospital,!Stockholm,!Sweden.!
Research%nurses%/%local%trial%coordinators:%
Esther!van!der!Heijden,!Naziha!Ghannouti;!Erasmus!MC!University!Medical!Center!
Rotterdam,!the!Netherlands.!Nadine!Fleitour,!Imke!Hooijenga;!Academic!Medical!Center!
Amsterdam,!the!Netherlands.!Corina!Puppels,!Wilma!Pellikaan;!Sint!Antonius!Hospital,!
Nieuwegein,!the!Netherlands.!Annet!Geerling;!Radboud!University!Nijmegen!Medical!
Center,!the!Netherlands.!Annemieke!Lindl#Velema;!Maastricht!University!Medical!Center,!
the!Netherlands.!Gina!van!Vemde;!Isala!Klinieken,!Zwolle,!The!Netherlands.!Ans!de!Ridder,!
Paut!Greebe,!University!Medical!Center!Utrecht,!the!Netherlands.!José!de!Bont#
Stikkelbroeck,!Sint!Elisabeth!Hospital,!Tilburg,!the!Netherlands.!Joke!de!Meris,!MC!
Haaglanden,!the!Hague,!the!Netherlands.!Kirsten!Janssen,!Leiden!University!Medical!Center,!
the!Netherlands.!Willy!Struijk,!HAGA!Hospital,!the!Hague,!the!Netherlands.!!
PhD%/%Medical%students:%
Silvan!Licher,!Nikki!Boodt,!Adriaan!Ros,!Esmee!Venema,!Ilse!Slokkers,!Raymie#Jayce!Ganpat,!
Maxim!Mulder,!Nawid!Saiedie,!Alis!Heshmatollah,!Stefanie!Schipperen,!Stefan!Vinken,!
Tiemen!van!Boxtel,!Jeroen!Koets;!Erasmus!MC!University!Medical!Center!Rotterdam,!the!
Netherlands.!!
! 4!
Merel!Boers,!Emilie!Santos,!Jordi!Borst,!Ivo!Jansen,!Manon!Kappelhof,!Marit!Lucas,!Ralph!
Geuskens,!Renan!Sales!Barros,!Roeland!Dobbe,!Marloes!Csizmadia;!Academic!Medical!
Center!Amsterdam,!the!Netherlands.! !
! 5!
Additional%Methods%
Intervention%%
The!method!of!IAT!was!left!to!the!discretion!of!the!local!interventionist.!The!same!applied!to!
the!type!of!mechanical!thrombectomy,!and!to!the!choice!for!general!anaesthesia.!
Approval!of!devices!by!the!steering!committee!was!based!on!CE!marking!or!FDA!approval,!
documented!evidence!of!safety!in!experienced!hands,!recanalization!rates!that!were!similar!
to!rates!with!other!mechanical!devices,!and!published!case!series!of!at!least!20!patients!with!
one!particular!type!of!device!in!a!representative!series!of!patients.!
Clinical%&%radiological%assessment%%
An!experienced!investigator!did!primary!outcome!assessment!by!means!of!a!telephonic!
interview.!If!a!patient!was!unavailable!or!unable!to!answer!the!questions,!a!proxy!or!
healthcare!provider!was!interviewed.!Written!reports!of!the!interviews!were!sent!to!two!
members!of!the!outcome!assessment!committee,!which!consisted!of!four!experienced!
vascular!neurologists!who!were!blinded!for!treatment!allocation.!The!score!on!the!90#day!
mRS!was!determined!after!review!of!these!telephone!interviews.!If!there!was!disagreement!
between!the!two!observers,!a!third!independent!observer,!who!was!also!blinded,!resolved!
differences!in!interpretation.!
NIHSS!assessment!was!done!by!the!treating!physicians.!They!received!web#based!video#
training.!
The!ASPECTS!is!a!10#point!quantitative!topographic!CT!scan!score!(range!0#10),!with!1!point!
subtracted!for!evidence!of!ischemic!change!in!each!defined!region.!The!mAOL!score!is!a!4#
point!scale,!original!designed!for!DSA,!but!modified!for!CTA,!which!ranges!from!grade!0!(No!
recanalization)!to!grade!3!(Complete!recanalization!of!the!primary!intracranial!occlusion).!
Trial%organization%
All!decisions!concerning!the!trial!design!and!protocol!had!to!be!approved!by!the!trial!
steering!committee,!which!met!at!least!once!a!year.!The!executive!committee,!consisting!of!
3!neuroradiologists,!3!neurologists,!and!4!PhD!students,!was!responsible!for!the!daily!
conduct!of!the!trial.!Central!and!local!research!nurses!organized!data!retrieval.!
Subcommittees!for!the!blinded!assessment!of!clinical!outcomes,!neuroimaging,!and!adverse!
events!acted!blinded!and!independently!of!the!executive!committee.!A!trial!statistician!had!
! 6!
access!to!all!data!and!prepared!unmasked!reports!for!the!data!monitoring!committee!
(DMC).!The!DMC!consisted!of!a!neurologist,!a!neuro#interventionist,!and!a!biostatistician.!
The!procedures!and!statistical!rules!for!DMC!review!are!described!in!the!trial!protocol!
(available!with!this!article!at!nejm.org).!
! !
! 7!
Supplemental%Results%and%Subgroup%analyses%
Baseline!characteristics!were!evenly!distributed!between!the!intervention!and!control!arms!
of!the!trial.!An!imbalance!existed!in!the!proportion!of!patients!with!left!hemisphere!strokes,!
which!were!more!represented!in!the!control!arm!(7.5%!absolute!difference).!Although!this!
imbalance!could!have!favored!the!intervention,!it!did!not!translate!into!differences!in!NIHSS!
scores!at!baseline.!Treatment!with!IV!alteplase!was!more!prevalent!(3.5%!absolute!
difference)!in!the!control!arm,!which!in!its!turn!may!favor!the!control!patients.!It!is!likely!
that!the!absolute!effect!of!these!imbalances!within!the!trial!population!was!minimal.!
The!point!estimates!for!treatment!effect!favored!intervention!regardless!of!NIHSS!score!
strata,!age!≥80!versus!<80!years,!presence!of!internal!carotid!artery!(ICA)!terminus!occlusion!
or!extracranial!ICA!occlusion,!time!from!randomization!≥120!versus!<120!minutes!and!the!
(non#prespecified)!subgroup!with!and!without!IV!alteplase!treatment!(Figure!S2).!
!!!!In!a!post#hoc!analysis!of!the!adjusted!treatment!effect!on!the!primary!outcome,!we!
replaced!“previous!stroke”!with!“pre#stroke!mRS”.!This!did!not!change!the!estimate!of!
treatment!effect!(acOR!1.62,!95%!CI:!1.18!to!2.23).!
! !
! 8!
Figure!S1.!CONSORT!flow!diagram:!Allocation,!crossovers!and!loss!to!follow#up!in!the!MR!
CLEAN!trial.!
Figure%S%1%CONSORT%flow%diagram%
RANDOMIZED (n=502)
ALLOCATION
Allocated to Intervention arm (n=233) Allocated to control arm (n=267)
Underwent catheter angiography (n=216) Received allocated standard treatment (n=266)
Did not undergo catheter angiography (n=17) Did not receive allocated standard treatment (n=1)
Reasons why intervention was withheld: Reason why allocation was violated:
- Clinical improvement before start of intervention (n=8) - Demanded treatment (n=1)
- Protocol violation from local investigators (n=6)
- No femoral access (n=1)
- Withdrawn consent for IAT (n=1)
- Hemodynamically unstable (n=1)
FOLLOW-UP
Lost to follow-up (n=0) Lost to follow-up (n=0)
ANALYSIS
Analyzed 233 out of 233 Analyzed 267 out of 267
The!overall!crossover!rate!was!18/500!(3.6%).!
! !
! 9!
Figure!S2!Subgroup!analyses!
Adjusted!effects!of!treatment!on!the!overall!distribution!of!the!mRS!in!prespecified!
subgroups.!Adjustment!were!made!for!age,!NIHSS!at!baseline,!time!to!randomization,!
previous!stroke,!atrial!fibrillation,!diabetes!mellitus!and!presence!of!carotid!T!occlusion.!!
Figure%S%2%Subgroup%analyses%
Age
<80 419 1.60 (1.13 to 2.28)
NIHSS
2-15 164 1.71 (0.96 to 3.02)
Onset to randomization
≥120 min 449 1.69 (1.21 to 2.38)
IV alteplase*
no 55 2.06 (0.69 to 6.13)
ASPECTS
0-4 28 1.09 (0.14 to 8.46)
0 1 2 3 4 5 6 7 8 9 10
*Exploratory!analysis.!
^Exploratory!analysis!based!on!extracranial!ICA!occlusion!as!reported!by!local!investigator.!
! 10!
!
!
Table!S1.!Overview!of!additional!clinical!characteristics!at!baseline!of!the!500!patients!
included!in!the!MR!CLEAN!trial,!by!treatment!allocation:!intervention!(intra#arterial!
treatment)!or!control!(no!intra#arterial!treatment).!
Table%S%1%Overview%of%additional%clinical%characteristics%
! 11!
Table
S2.
Number
of
patients
treated
and
treatment
details
by
center.
Table S 2 Number of patients treated and treatment details by center
12
Table!S3.!Definition!and!distribution!of!modified!Arterial!Occlusive!Lesion!(mAOL)!score!on!CT!
angiography!after!24!hours.!
Table&S&3&Definition&and&distribution&of&modified&Arterial&Occlusive&Lesion&(mAOL)&score&
0!(No!recanalization!of!the!primary!intracranial!
24!(12.8%)! 68!(32.9%)!
occlusion)!–!n.!(%)!
1!(Incomplete!or!partial!recanalization!of!the!
primary!intracranial!occlusion!without!contrast! 6!(3.2%)! 20!(9.6%)!
passage)!–!n.!(%)!
2!(Incomplete!or!partial!recanalization!with!contrast!
16!(8.6%)! 49!(23.7%)!
passage)!–!n.!(%)!
3!(Complete!recanalization!of!the!primary!
141!(75.4%)! 70!(33.8%)!
intracranial!occlusion)!–!n.!(%)!
! !
! 13!
Table!S4.!Definition!and!distribution!of!modified!Thrombolysis!in!Cerebral!Infarction!(mTICI)!score!in!
patients!allocated!to!the!intervention!arm!(N=233).!If!post!treatment!lateral!DSA!images!were!of!
insufficient!quality!or!missing,!the!highest!score!possible!was!mTICI!2a!(N=15).!
Table&S&4&Definition&and&distribution&of&mTICI&score&
1!(antegrade!flow!past!the!initial!occlusion,!
but!limited!distal!branch!filling!with!little!or! 11!(6.0%)! 11!(5.6%)!
slow!distal!reperfusion)!–!n.!(%)!
2a!(antegrade!reperfusion!of!less!than!half!
of!the!previously!ischemic!territory)!–!n.! 4!(2.2%)! 43!(21.9%)!
(%)!
2b!(antegrade!reperfusion!of!more!than!
half!of!the!previously!ischemic!territory)!–! 0!(0%)! 68!(34.7%)!
n.!(%)!
3!(complete!antegrade!reperfusion!of!the!
previously!ischemic!territory,!with!absence!
0!(0%)! 47!(24.0%)!
of!visualized!occlusion!in!all!distal!
branches)!–!n.!(%)!
! 14!
!
Table!S5.!Breakdown!of!the!primary!outcome!and!treatment!effect!in!the!500!MR!CLEAN!patients.!The!table!lists!numbers!of!patients!and!percentages!in!
each!treatment!group,!type!of!effect!parameter!(OR!or!linear!regression!coefficient),!unadjusted!and!adjusted!for!age,!NIHSS!at!baseline,!time!to!
randomization,!previous!stroke,!atrial!fibrillation,!diabetes!mellitus!and!presence!of!ICA!terminus!occlusion.!
Table&S&5&Breakdown&of&the&primary&outcome&and&treatment&effect&
! 15!
Table!S6.!Number!of!patients!with!imputed!values!and!imputation!method!for!baseline!variables,!used!
for!adjustment!of!treatment!effect.!
Table&S&6&Number&of&patients&with&imputed&values&
&
Age! Median! 0! A! A!
NIHSS!total!score*+! ! 0! 0! 0!
!!!Item!1a!LOC!responsiveness! Mode! 1! 0! 0!
!!!Item!1b!LOC!questions! Mode! 1! 0! 3!
!!!Item!1c!LOC!commands! Mode! 2! 0! 1!
!!!Item!2!Horizontal!eye!movement! Mode! 1! 1! 4!
!!!Item!3!Visual!field!test! Mode! 5! 1! 8!
!!!Item!4!Facial!palsy! Mode! 1! 1! 2!
!!!Item!5a!Motor!arm!left! Mode! 0! 0! 0!
!!!Item!5b!Motor!arm!right! Mode! 0! 1! 0!
!!!Item!6a!Motor!leg!left! Mode! 0! 0! 0!
!!!Item!6b!Motor!leg!right! Mode! 0! 1! 0!
!!!Item!7!Limb!ataxia! Mode! 6! 4! 5!
!!!Item!8!Sensory! Mode! 9! 5! 9!
!!!Item!9!Language! Mode! 0! 1! 0!
!!!Item!10!Speech!! Mode! 0! 1! 1!
!!!Item!11!Extinction!and!inattention! Mode! 4! 3! 5!
Time!since!onset!to!randomization!! Median! 2!! A! A!
Previous!stroke! Mode! 0! A! A!
Atrial!fibrillation! Mode! 0! A! A!
Diabetes!mellitus! Mode! 0! A! A!
ICA!terminus!occlusion! Mode! 1! A! A!
*at!24!hours!20!patients!had!completely!missing!NIHSS!assessments;!these!data!were!not!imputed.!
+!
at!5A7!days!74!patients!had!completely!missing!NIHSS!assessments;!these!data!were!not!imputed.!
! 16!
Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for acute
ischemic stroke. N Engl J Med. DOI: 10.1056/NEJMoa1411587
This
supplement
contains
the
following
items
1.
Protocol
th
a. Original
protocol,
(first
version
receiving
MAC
approval)
version
3.0
date
February
20
2010
p
2
-‐
58
th
b. Final
protocol,
version
3.5
date
June
11
2014
p
59
-‐
121
c. Summary
of
changes,
chronologically
displayed
in
appendix
5
to
9
of
the
Final
protocol
p
106
–
111
i. Original
protocol:
Version
3.0,
date
February
20,
2010
ii. Amendment
1:
Version
3.1,
date
March
6,
2012
iii. Amendment
2
:
Version
3.2,
date
December
12,
2012
iv. Amendment
3:
Version
3.3,
date
February
26,
2013
v. Amendment
4:
Version
3.4,
date
September
5,
2013
vi. Amendment
5:
Version
3.5,
date
June
11,
2014
2.
Statistical
analysis
plan
a. Original
statistical
analysis
plan
(SAP)
is
listed
in
Appendix
10
of
the
Final
protocol
p
112
-‐
117
1 th
b. Latest
version
of
the
statistical
analysis
plan
as
published
in
Trials ,
version
3.1
July
14
2014
p
122
–
127
c. Summary
of
changes
p
128
1
Fransen
PS,
Beumer
D,
Berkhemer
OA,
et
al.
MR
CLEAN,
a
multicenter
randomized
clinical
trial
of
endovascular
treatment
for
acute
ischemic
stroke
in
the
Netherlands:
study
protocol
for
a
randomized
controlled
trial.
Trials
2014;15:343.
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
MR
CLEAN-‐Multicenter
Randomized
Clinical
trial
of
Endovascular
treatment
for
Acute
ischemic
stroke
in
the
Netherlands.
Protocol
ID
NTR1804
Version 3.0
Coordinating
investigator
and
executive
Diederik
WJ
Dippel,
neurologist
Erasmus
MC
University
Medical
Center
Rotterdam,
PO
Box
2040
committee
of
the
trial
3000
CA
Rotterdam,
The
Netherlands.
T
+31
10
7043979;
F
+31
10
7044721
E
d.dippel@erasmusmc.nl.
Yvo
B
Roos,
neurologist
AMC
Amsterdam
Charles
Majoie,
radiologist,
AMC
Amsterdam
Aad
van
der
Lugt,
radiologist,
Erasmus
MC
Rotterdam
Robert
van
Oostenbrugge,
neurologist,
Maastricht
UMC
Wim
van
Zwam,
radiologist,
Maastricht
UMC
Sponsor
Raad
van
Bestuur
Erasmus
MC
University
Medical
Center
Rotterdam.
2
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
3
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
4
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
Diederik
W
Dippel,
Charles
B
Majoie,3
Aad
van
der
Lugt,2
Wim
van
Zwam5
Robert
J
van
Oostenbrugge,6
Puck
Fransen,1,2
JR2,3,4
JR3,5,6
and
Yvo
B
Roos,4
for
the
MR
CLEAN
investigators.*
Departments
of
Neurology1
and
Radiology2
of
Erasmus
MC
University
Medical
Center
Rotterdam,
Radiology3
and
Neurology4
of
the
Academisch
Medisch
Centrum,
Amsterdam,
The
Netherlands,
and
Radiology5
and
Neurology6
of
the
Maastricht
University
Medical
Center,
The
Netherlands.
*
The
MR
CLEAN
investigators
are
listed
in
the
appendix.
Correspondence:
Diederik
WJ
Dippel,
Dept
of
Neurology,
Erasmus
MC
University
Medical
Center
Rotterdam,
PO
Box
2040
3000
CA
Roterdam,
The
Netherlands.
T
+31
10
7043979;
F
+31
10
7044721
E
d.dippel@erasmusmc.nl.
Version:
3.0
Date
February
20,
2010
5
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
Acknowledgments
.............................................................................................................................................................................................................
12
1.4 Needed: a randomized clinical trial of endovascular treatment in acute ischemic stroke .......................................................... 16
6
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
Table 2: randomized clinical trials of intra-‐arterial thrombolysis ................................................................................................................. 37
Table 3 controlled studies and case series of i.v. + i.a. alteplase ................................................................................................................. 38
Table 4 studies of mechanical treatment in acute ischemic stroke ............................................................................................................ 40
Table
5B.
Thrombolysis
in
Cerebral
Infarction
(TICI)
scale.
.........................................................................................................................
42
45
Table
5C
Clot
burden
score
for
CTA
and
MRA
.................................................................................................................................................
43
46
Appendix
3
Recommendations
of
the
Steering
committee
with
regard
to
endovascular
treatment
procedures,
thrombolytic
agents,
and
type
of
mechanical
thrombectomy.
...............................................................................................................................................
50
Table
A1.
Optimal
Time-‐path
for
treatment
and
inclusion
in
MR
CLEAN
of
patients
with
acute
ischemic
stroke
and
relevant
anterior
circulation
arterial
inclusion
.....................................................................................................................................................................
50
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase .................................. 52
Table
A3.
List
of
mechanical
thrombectomy
devices
that
are
available
in
The
Netherlands,
their
mode
of
action
and
current
status.
................................................................................................................................................................................................................................
53
Figure 3. Randomization and inclusion of patients in the trial ...................................................................................................................... 57
7
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
1.4 Needed: a randomized clinical trial of endovascular treatment in acute ischemic stroke .......................................................... 73
8
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
Table 2: randomized clinical trials of intra-‐arterial thrombolysis ................................................................................................................. 92
Table 3 controlled studies and case series of i.v. + i.a. alteplase ................................................................................................................. 93
Table 4 studies of mechanical treatment in acute ischemic stroke ............................................................................................................ 94
Table
5B.
modifed
Thrombolysis
in
Cerebral
Infarction
(TICI)
scale.
.......................................................................................................
95
45
Table
5C
Clot
burden
score
for
CTA
and
MRA
.................................................................................................................................................
96
46
Appendix
3
Recommendations
of
the
Steering
committee
with
regard
to
endovascular
treatment
procedures,
thrombolytic
agents,
and
type
of
mechanical
thrombectomy.
.............................................................................................................................................
102
Table
A1.
Optimal
Time-‐path
for
treatment
and
inclusion
in
MR
CLEAN
of
patients
with
acute
ischemic
stroke
and
relevant
anterior
circulation
arterial
inclusion
...................................................................................................................................................................
102
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase ................................ 104
Table
A3.
List
of
mechanical
thrombectomy
devices
that
are
available
in
The
Netherlands,
their
mode
of
action
and
current
status.
..............................................................................................................................................................................................................................
105
APPENDIX 5: Protocol amendment MR CLEAN trial; substantial Protocol 3.1. ..................................................................................... 106
APPENDIX 6 : PROTCOL AMENDMENT MR CLEAN TRIAL SUBSTANTIAL PROTOCOL 3.2 .................................................................... 107
Appendix 7: PROTCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.3 ..................................................................... 108
Appendix 8: PROToCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.4 .................................................................. 110
9
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
Appendix 9: PROToCOL AMENDMENT MR CLEAN TRIAL; PROTOCOL 3.5 .............................................................................................. 110
Time path of the analyses and locking of the database. .................................................................................................................................... 116
Figure 3. Randomization and inclusion of patients in the trial .................................................................................................................... 120
10
Version
3.0
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20,
2010
MR
CLEAN
Trial
protocol
Time path of the analyses and locking of the database. .................................................................................................................................... 126
11
Version
3.0
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20,
2010
MR
CLEAN
Trial
protocol
ACKNOWLEDGMENTS
MR
CLEAN
is
partly
funded
by
the
Netherlands
Heart
Foundation
(2008T030),
and
by
unrestricted
grants
from
AngioCare
BV,
EV3®,
MEDAC
Gmbh/LAMEPRO
,
Penumbra
Inc
and
Concentric
Medical
/TOP
Medical
BV.
The
study
is
designed,
and
will
be
conducted,
analyzed,
and
interpreted
by
the
investigators
independently
of
all
sponsors.
12
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
SUMMARY
DESIGN
MR
CLEAN
is
a
pragmatic
phase
III
multicenter
randomized
clinical
trial
with
blinded
outcome
assessment.
The
intervention
contrast
is
intra-‐arterial
treatment
versus
no
intra-‐
arterial
treatment.
STUDY
POPULATION
Patients
should
have
a
clinical
diagnosis
of
acute
ischemic
stroke,
MRI1
or
CT
ruling
out
intracerebral
hemorrhage,
a
score
on
the
National
Institutes
of
Health
Stroke
Scale
(NIHSS)
of
2
points
or
more,
a
relevant
intracranial
arterial
occlusion,
demonstrated
by
neuro-‐
imaging
and
the
possibility
to
start
endovascular
treatment
within
6
hours
after
stroke
onset.
INTERVENTION
Endovascular
treatment
may
consist
of
intra-‐arterial
thrombolysis
with
urokinase
or
alteplase,
mechanical
treatment
or
both.
Mechanical
treatment
refers
to
retraction
or
aspiration
of
the
thrombus
with
a
catheter
guided
device,
or
stenting.
The
exact
choice
of
endovascular
treatment
modality
for
each
patient
is
left
to
the
discretion
of
the
local
investigator
and
treating
physicians.
The
steering
committee
will
provide
recommendations
and
guidelines
for
treatment
and
selection
of
patients
in
the
study.
Background
medical
management
is
delivered
according
to
national
standards
and
guidelines.
It
may
include
intravenous
alteplase
within
the
first
4.5
hours
after
onset.
1
All
abbreviations
are
listed
in
Table
1.
13
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3.0
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20,
2010
MR
CLEAN
Trial
protocol
DISCUSSION
MR
CLEAN
is
a
pragmatic
trial.
Inclusion
of
patients
will
take
4
years,
and
starts
early
in
2010.
Key
words:
alteplase,
endovascular
treatment,
acute
ischemic
stroke,
randomized
controlled
trial
14
Version
3.0
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20,
2010
MR
CLEAN
Trial
protocol
15
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
patients
had
been
included.
More
patients
with
intra-‐arterial
treatment
than
patients
with
intravenous
treatment
showed
recanalization
and
good
outcome,
but
the
effect
was
not
statistically
significant.19
Several
non-‐randomized
studies
with
historical
controls,20
or
controls
in
other
centers,21
suggested
a
benefit
of
intra-‐arterial
thrombolysis.
1.4
NEEDED:
A
RANDOMIZED
CLINICAL
TRIAL
OF
ENDOVASCULAR
TREATMENT
IN
ACUTE
ISCHEMIC
STROKE
16
Version
3.0
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20,
2010
MR
CLEAN
Trial
protocol
We
conclude
from
this
overview
that
intra-‐arterial
treatment,
either
with
a
thrombolytic
agent
or
by
mechanical
means
is
able
to
recanalize
acutely
occluded
cerebral
arteries
in
selected
patients,
within
reasonable
safety
margins.
Whether
this
is
the
case
in
an
unselected
sample
of
patients
with
acute
ischemic
stroke
caused
by
occlusion
is
likely,
but
unproven.
A
randomized
clinical
trial
addressing
the
question
whether
intra-‐arterial
treatment
improves
neurological
outcome
in
patients
with
a
relevant
occlusion
in
the
intracranial
proximal
anterior
circulation
is
therefore
needed.
For
the
trial
results
to
be
generalizable
and
representative
of
what
is
state
of
the
art
approach
in
intra-‐arterial
treatment,
the
trial
design
should
accommodate
the
possibility
to
use
local
fibrinolytics
and
or
mechanical
thrombectomy
devices,
for
a
broad
range
of
patients
with
acute
ischemic
stroke
caused
by
a
proximal
thrombo-‐embolic
occlusion
of
one
of
the
intracranial
arteries
belonging
to
the
anterior
circulation.
Important
subgroups
to
whom
this
question
of
effectiveness
and
safety
applies
are
patients
who
have
been
treated
unsuccessfully
with
intravenous
thrombolysis,
patients
who
can
be
treated
within
6
hours,
but
do
not
meet
the
time
window
requirements
for
intravenous
thrombolysis,
and
patients
with
contra-‐indications
for
intravenous
and/or
intra-‐arterial
thrombolytic
treatment
(thrombectomy
only).
To
answer
this
question,
we
initiated
a
large
multicenter
pragmatic
trial
of
intra-‐arterial
treatment
(by
means
of
alteplase
and
or
mechanical
treatment)
versus
standard
medical
treatment,
in
patients
with
acute
ischemic
stroke
of
less
than
6
hours
of
onset,
the
MR
CLEAN
study.
The
trial
applies
the
grey
area
principle:
when
a
patient’s
clinical
profile
meets
inclusion
and
exclusion
criteria,
and
according
to
investigator
and
treating
physician
there
is
sufficient
uncertainty
concerning
the
question
whether
the
patient
should
receive
intra-‐arterial
treatment,
the
patient
is
eligible
for
inclusion
in
the
trial.
2.
OBJECTIVES
The
primary
objective
of
this
study
is
to
estimate
the
effect
of
endovascular
treatment
on
overall
functional
outcome
after
acute
ischemic
stroke
of
less
than
six
hour
duration,
in
patients
with
a
symptomatic
occlusion.
The
secondary
objectives
are
to
assess
the
safety
of
endovascular
treatment
with
regard
to
the
occurrence
of
hemorrhagic
and
ischemic
complications,
the
efficacy
with
regard
to
obtaining
recanalization,
and
to
evaluate
predictors
of
recanalization,
including
imaging
aspects
and
hemostatic
parameters.
Moreover,
we
want
to
assess
the
safety
and
efficacy
of
different
types
of
endovascular
treatment
(i.e.
mechanical
treatment,
intra-‐arterial
thrombolysis)
different
combinations
of
treatment
(i.e.
with
intravenous
alteplase)
and
different
timings
of
treatment.
Tertiary
objectives
are
to
carry
out
case
studies
of
implementation
strategies
and
loco-‐regional
solutions
for
barriers
to
the
delivery
of
endovascular
treatment
for
acute
ischemic
stroke
and
to
collect
data
for
cost-‐effectiveness
analysis
of
endovascular
treatment
compared
with
standard
treatment.
3.
STUDY
DESIGN
This
is
a
multicenter
clinical
trial
with
randomized
treatment
allocation,
open
label
treatment
and
blinded
endpoint
evaluation
(PROBE
design).
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The
intervention
contrast
is
endovascular
treatment
(alteplase
or
urokinase,
and/or
mechanical
treatment)
versus
no
endovascular
treatment.
The
treatment
is
provided
in
addition
to
best
medical
management,
including
intravenous
thrombolysis.
The
study
will
run
in
at
least
10
large
hospitals
in
the
Netherlands
for
a
period
of
five
years
(4
years
of
patient
inclusion),
and
starts
in
2010.
4. STUDY POPULATION
4.1
POPULATION
Patients
over
18
years
old,
with
acute
ischemic
stroke,
a
symptomatic
anterior
proximal
artery
occlusion
which
can
be
treated
within
6
hours
after
stroke
onset
are
eligible
for
participation
in
this
trial.
INCLUSION
CRITERIA
• A
clinical
diagnosis
of
acute
stroke,
with
a
deficit
on
the
NIH
stroke
scale
of
2
points
or
more.
• CT
or
MRI
scan
ruling
out
intracranial
hemorrhage.
• Intracranial
arterial
occlusion
of
the
distal
intracranial
carotid
artery
or
middle
(M1/M2)
or
anterior
(A1/A2)
cerebral
artery,
demonstrated
with
CTA,
MRA,
DSA
or
transcranial
Doppler/duplex
(TCD).
• The
possibility
to
start
treatment
within
6
hours
from
onset.
• Informed
consent
given.
• Age
18
or
over.
• Laboratory
evidence
of
coagulation
abnormalities,
i.e.
platelet
count
<40
x
109/L,
APTT>50
sec
or
INR
>3.0.
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• Cerebral
infarction
in
the
distribution
of
the
relevant
occluded
artery
in
the
previous
6
weeks.
• History
of
intracerebral
hemorrhage.
• Severe
head
injury
(contusion)
in
the
previous
4
weeks.
• Clinical
or
laboratory
evidence
of
coagulation
abnormalities,
i.e.
platelet
count
<90
x
109/L,
APTT>50
sec
or
INR
>1.7.
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6.METHODS
PRIMARY
OUTCOME
The
primary
outcome
is
the
score
on
the
modified
Rankin
scale
at
90
days
(Table
5a).
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SECONDARY OUTCOMES
IMAGING PARAMETERS
• Vessel
recanalization
at
24
hours
after
treatment,
assessed
by
CTA
or
MRA.
The
criteria
for
recanalization
on
CTA
or
MRA
are
based
on
a
simplified
TICI
score
(Table
5b),45
and
the
clot
burden
score,
proposed
by
Puetz
et
al
(Table
5c)46.
• Infarct
size
assessed
by
CT
on
day
5-‐7,
using
standard
methods,
including
manual
tracing
of
the
infarct
perimeter
and
semiautomated
pixel
thresholding.47,
48
Infarct
size
at
day
5-‐7
will
be
compared
with
plain
CT
and
perfusion
CT
results
(if
available)
at
baseline.
• CTA
or
MRA
at
24
hours
will
be
compared
with
baseline
vessel
imaging
data,
to
estimate
the
recanalization
rate.
Perfusion
CT
at
baseline
is
optional,
but
available
at
most
centers.
Clinical
parameters
CLINICAL PARAMETERS
• NIHSS 49, including NIH supplemental motor score,50 at 24 hours.
FUNCTIONAL OUTCOME
• Score on the Academic Linear Disability Scale at 90 days53.
• Score
on
the
Telephone
Interview
for
Cognitive
Status
(TICS)
54,
54-‐57
The
90-‐days
follow-‐up
will
be
conducted
by
telephone
interview,
through
the
central
trial
office.
SAFETY
PARAMETERS
Safety
is
an
issue
of
concern,
as
the
experience
with
the
intervention,
overall,
and
within
the
participating
centers,
is
limited.
Safety
parameters
include
hemorrhagic
complications,
and
short
term
outcome
(mortality,
Barthel
index
and
NIHSS
at
24
hours
and
at
one
week
or
discharge).
As
we
will
make
use
of
web-‐based
data-‐entry,
these
data
will
be
available
on
short
notice.
The
primary
safety
parameter
will
be
neurologic
deterioration
within
24
hours
from
inclusion
in
the
study.
Neurological
deterioration
is
defined
as
any
decline
in
NIHSS
of
more
than
2
points.
In
these
patients,
urgent
brain
CT
is
mandatory.
This
serious
adverse
event
will
be
further
classified
as
due
to
intracranial
hemorrhage,
ischemia
or
other
(undetermined)
cause.
A
full
list
of
serious
adverse
events
is
provided
in
section
7.1
Adverse
events.
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If
the
local
investigator,
or
other
member
of
the
team
at
a
trial
centre
has
a
concern
about
the
outcome
of
their
trial
procedures,
they
should
inform
the
MR
CLEAN
trial
office,
which
will
organize
a
blinded
assessment
of
the
relevant
outcome
events.
This
will
be
submitted
by
the
central
office
to
the
chairman
of
the
data
monitoring
committee,
who
may
recommend
further
action,
such
as
suspending
randomization
at
the
centre.
Similarly,
the
database
manager
at
the
trial
office
will
monitor
outcome
events
and
if
there
are
three
consecutive
deaths
or
three
consecutive
serious
adverse
events
at
a
single
centre
within
30
days
of
treatment
in
the
same
arm
of
the
study,
then
assessment
of
the
events
will
be
triggered.
A
cumulative
death
rate
of
more
than
50%
or
a
cumulative
serious
adverse
event
rate
exceeding
20%
over
10
cases
during
hospital
admission
would
also
trigger
careful
assessment
of
the
relevant
outcome
events.
6.2
RANDOMIZATION
The
randomization
procedure
will
be
computer-‐
and
web-‐based,
using
permuted
blocks.
Back-‐up
by
telephone
will
be
provided.
Randomization
is
allowed
when
the
occlusion
has
been
established
by
CTA,
MRA,
DSA
or
TCD.
Selection
of
patients
for
randomization
follows
the
grey
area
principle.
Randomization
will
be
stratified
for
center,
use
of
intravenous
alteplase,
planned
treatment
modality
(mechanical
thrombectomy
or
not)
and
stroke
severity,(NIHSS
>14
or
not).
Patients
with
contra-‐indications
for
intravenous
thrombolysis
are
allowed
into
the
trial.
This
concerns
patients
who
cannot
be
treated
within
4.5
hours
from
onset,
but
only
in
the
4.5
to
6
hour
interval,
and
patients
with
either
major
surgery,
gastrointestinal
bleeding
or
urinary
tract
bleeding
within
the
previous
2
weeks,
or
arterial
puncture
at
a
non-‐compressible
site
within
the
previous
7
days.
Patients
with
exclusion
criteria
for
intra-‐arterial
thrombolysis
are
also
allowed
into
the
trial
.
They
can
be
included
and
randomized
for
endovascular
treatment
or
no
endovascular
treatment.Treatment
with
mechanical
thrombectomy
is
allowed,
but
intra-‐arterial
thrombolysis
is
not
allowed
in
these
patients.
The
treating
physicians
are
free
to
change
the
actual
mode
of
treatment
during
the
procedure,
as
long
as
they
comply
with
the
treatment-‐
specific
exclusion
criteria
and
recommended
devices.
6.3
BLINDING
It
will
not
be
possible
to
view
the
treatment
allocation
before
the
patient
is
registered
in
the
study
database,
nor
will
it
be
possible
to
remove
the
patient
from
the
study
base
after
treatment
assignment
has
become
known.
Both
patient
and
treating
physician
will
be
aware
of
the
treatment
assignment.
Information
on
outcome
at
three
months
will
be
assessed
through
standardized
forms
and
procedures.
Assessment
of
outcome
on
the
modified
Rankin
scale
will
be
based
on
this
information,
by
assessors
who
are
blind
to
the
treatment
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allocation.
Results
of
neuroimaging
will
be
also
assessed
in
a
blinded
manner.
Information
on
treatment
allocation
will
be
kept
separate
from
the
main
study
database.
The
steering
committee
will
be
kept
unaware
of
the
results
of
interim
analyses
of
efficacy
and
safety.
The
trial
statistician
will
combine
data
on
treatment
allocation
with
the
clinical
data
in
order
to
report
to
the
data
monitoring
committee
(DMC).
FOLLOW-‐UP
DATA
At
24
hours,
a
clinical
examination
including
NIH
stroke
scale
assessment
will
be
carried
out.
Also,
all
patients
will
undergo
CTA
or
MRA
imaging.
At
day
5-‐7
all
patients
will
undergo
CT
or
MRI.
Raw
data
will
be
forwarded
to
the
trial
office
for
blind
evaluation.
At
1
week,
clinical
status,
NIH
stroke
scale
score
and
adverse
events
will
be
reported
as
well
as
discharge
destination,
in
order
to
enable
the
trial
office
to
conduct
the
final
3-‐month
follow-‐up
by
telephone
interview.
The
standardized
telephone
interview
will
include
a
short
questionnaire
based
on
the
three
simple
questions,
assessment
of
modified
Rankin
Scale,
Academic
Linear
Disability
Scale,
Barthel
Index,
TICS
and
Euroqol5D.51-‐53,
60-‐62.
WITHDRAWAL
Patients
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
or
stop
the
allocated
intervention
for
urgent
medical
reasons.
Every
attempt
will
be
made
to
complete
follow-‐up
in
these
patients.
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co-‐principal
investigators,
and
study-‐coordinator.
The
post
of
study
coordinator
will
be
manned
by
each
of
three
junior-‐researchers,
taking
turns.
The
study-‐coordinator
is
responsible
for
running
the
trial
on
a
day-‐to-‐day
basis,
and
will
report
to
the
executive
committee.
The
executive
committee
will
meet
on
a
bi-‐monthly
basis.
The
steering
committee
will
meet
at
least
annually.
The
steering
committee
meeting
is
chaired
by
the
principal
investigator
(DD).
Other
important
committees
are
the
neuro-‐imaging
assessment
committee,
the
functional
outcome
adjudication
committee
and
the
serious
adverse
event
adjudication
committee.
The
trial
office
is
located
in
Rotterdam,
Erasmus
MC
University
Medical
Center.
The
neuro-‐
imaging
assessment
unit
is
located
in
AMC,
Amsterdam.
7.SAFETY REPORTING.
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justify
halting,
or
modifying,
the
study
prematurely.
This
criterion
has
the
practical
advantage
that
the
number
of
interim
analyses
is
of
little
importance.
8.
STATISTICAL
ANALYSES
Baseline
characteristics
will
be
summarized
by
means
of
simple
descriptive
statistics.
The
main
analysis
of
this
trial
consists
of
a
single
comparison
between
the
trial
treatment
groups
of
the
primary
outcome
after
90
days.
The
analysis
will
be
based
on
the
intention-‐to-‐treat
principle.
The
primary
effect
parameter
should
take
the
whole
range
of
the
modified
Rankin
scale
(mRS)
into
account
and
is
defined
as
the
relative
risk
for
improvement
on
the
mRS
estimated
as
an
odds
ratio
with
ordinal
logistic
regression.63
Multivariable
regression
analysis
will
be
used
to
adjust
for
chance
imbalances
in
main
prognostic
variables
between
intervention
and
control
group,
such
as
age,
stroke
severity
(NIHSS),
time
since
onset,
ischemic
stroke
subtype
(lacunar
vs
non-‐lacunar)
previous
stroke,
atrial
fibrillation
and
diabetes
mellitus.
Secondary
effect
parameters
will
be
the
improvement
according
to
the
classical
dichotomizations
of
the
modified
Rankin
scale
at
0-‐1
vs
2-‐6
and
0-‐2
vs
3-‐6,
the
presence
of
vessel
patency
on
CTA,
MRA
or
DSA
at
24
hours,
and
the
score
on
the
NIHSS
at
24
hours
and
1
week
or
discharge.
With
regard
to
the
range
of
secondary
outcome
parameters
we
will
use
simple
2x2
tables,
two-‐group
t-‐tests,
Mann-‐Whitney
tests,
and
multivariable
linear
and
logistic
regression
models,
where
appropriate.
In
all
analyses,
statistical
uncertainty
will
be
quantified
by
means
of
95%
confidence
intervals.
Subgroup
analyses
will
be
carried
out
to
estimate
the
effect
intra-‐arterial
thrombolysis,
mechanical
treatment
and
combination
therapy.
Although
the
size
of
this
study
will
not
allow
for
precise
estimates
of
treatment
effect
in
subgroups,
we
will
assess
heterogeneity
of
effects,
and
analyze
consistency
of
effects
on
secondary
outcomes.
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be
obtained
from
a
legal
representative.
Because
the
study
physicians
are
also
involved
in
the
clinical
care
of
patients
with
acute
ischemic
stroke,
it
appears
inevitable
that
in
some
occasions
the
study
physician
will
also
be
the
patient’s
treating
physician.
As
this
is
an
acute
stroke
trial
with
a
narrow
time
window
for
the
start
of
treatment,
and
because
of
time-‐consuming
study-‐related
procedures
after
informed
consent
will
be
obtained,
the
time
for
consideration
of
participation
in
the
trial
will
be
limited
to
the
first
few
hours
after
stroke
onset.
Even
within
this
time
frame,
a
decision
on
participation
should
preferably
be
taken
as
soon
as
possible,
at
least
within
30
minutes.
Especially
patients
with
large
cortical
infarcts
may
not
be
able
to
judge
the
pros
and
cons
of
participation
in
the
trial
sufficiently,
most
often
because
of
aphasia.
As
aphasia
is
present
in
approximately
25%
of
the
patients
with
acute
stroke
and
because
patients
with
large
cortical
infarcts
may
benefit
most
from
intra-‐arterial
treatment
on
theoretical
grounds,
it
may
be
considered
inappropriate
to
exclude
these
patients
from
the
trial.
Incapacitated
patients
in
the
control
group
are
treated
according
to
current
standards
and
participation
in
the
trial
does
therefore
not
carry
a
risk;
the
burden
caused
by
the
additional
investigations
is
considered
minimal.
10.1
PRIVACY
All
included
patients
will
be
assigned
a
unique
number.
Name
and
address
will
be
stored
separately
from
the
study
data.
Consent
with
participation
in
the
study
will
be
asked
from
all
patients
after
presenting
them
with
standard
written
forms.
The
information
describes
the
purpose
of
the
study,
interventions,
potential
hazards
and
benefits
and
the
procedures
for
recording
of
clinical
information
and
three
month
follow
up.
10.2
SUBSTUDIES
Substudies
will
be
carried
out
on
the
role
of
hemostatic
factors
as
effect
modifiers
in
endovascular
treatment
(van
Oostenbrugge),
on
costs
and
cost-‐effectiveness
of
endovascular
treatment
(Roos),
and
on
clinical
and
radiological
predictors
of
recanalization
(Majoie)
and
functional
outcome
after
treatment
(Dippel).
Interobserver
and
validation
studies
of
rapid
reperfusion
scores
will
be
carried
out.
The
MR
CLEAN
investigators
share
a
26
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
positive
attitude
towards
the
conductance
of
substudies
in
general.
Proposals
for
substudies
will
be
discussed
within
the
executive
committee
and
decisions
will
be
made
by
the
steering
committee.
27
Version
3.0
February
20,
2010
MR
CLEAN
Trial
protocol
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2003
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KJ.
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protocol
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M,
de
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RJ,
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R.
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item
response
theory
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patient
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Qual
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2005
December
29;3:83.:83.
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Validity
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Telephone
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post-‐stroke
subjects.
Int
J
Geriatr
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2004
January;19(1):75-‐9.
(55)
Cook
SE,
Marsiske
M,
McCoy
KJ.
The
use
of
the
Modified
Telephone
Interview
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Cognitive
Status
(TICS-‐M)
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the
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mild
cognitive
impairment.
J
Geriatr
Psychiatry
Neurol
2009
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L,
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Chui
H,
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V.
Validation
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based
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dementia.
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2005;5(1):8.
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RO,
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YE,
Pankratz
VS,
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TJ,
Petersen
RC,
Rocca
WA.
Validation
of
the
Telephone
Interview
for
Cognitive
Status-‐modified
in
Subjects
with
Normal
Cognition,
Mild
Cognitive
Impairment,
or
Dementia.
Neuroepidemiology
2009
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5;34(1):34-‐42.
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CJ,
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generalized
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Costing
in
economic
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2002;20(7):443-‐54.
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H,
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PM.
Validity
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reliability
of
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questions
in
assessing
short-‐
and
long-‐term
outcome
in
Norwegian
stroke
patients.
Cerebrovasc
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2001;11(4):305-‐10.
(61)
Dorman
P,
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M,
Sandercock
P.
Are
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modified
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a
valid
and
reliable
measure
of
health
related
quality
of
life
after
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United
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Collaborators
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2000
October;69(4):487-‐93.
(62)
van
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JC,
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PJ,
Visser
MC,
Schouten
HJ,
van
GJ.
Interobserver
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the
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1988
May;19(5):604-‐7.
(63)
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GD,
Barer
D,
Choi
S,
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H,
Gregson
B,
Lees
KR,
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EW,
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GS,
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GM,
Weir
CJ.
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2005
May;22(5):511-‐7.
(64)
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B,
Fricbergs
J.
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Am
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2001
February
1;22(2):352-‐8.
33
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3.0
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2010
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CLEAN
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protocol
(65)
The
IMS
Study
Investigators.
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Intravenous
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Intra-‐Arterial
Recanalization
for
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Stroke
2004
April
1;35(4):904-‐11.
(66)
Halkes
PH,
van
GJ,
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LJ,
Koudstaal
PJ,
Algra
A.
Aspirin
plus
dipyridamole
versus
aspirin
alone
after
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ischaemia
of
arterial
origin
(ESPRIT):
randomised
controlled
trial.
Lancet
2006
May
20;367(9523):1665-‐73.
34
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TABLES
Abbreviation Description
BI Barthel index
CT Computed tomography
MI Myocardial infarction
Version
3.0
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20,
2010
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TIMI
Thrombolysis
in
Myocardial
Infarction
36
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3.0
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20,
2010
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CLEAN
Trial
protocol
17
MELT
Ia
urokinase
+/-‐
mechanical
thrombectomy
vs
114
53%
vs
(n.r.)*
29/57
vs
35/57
11%
0.8
(0.6
–
control
1.2)
19
SYNTHESIS
IA
alteplase
w/wo
MERCI
vs
I.V.
alteplase,
both
54
NR
52%
vs72%
19%
0.7
(0.5
-‐1.1)
0.9
mg/kg
ARR=absolute risk reduction; RR= relative risk; mRS= modified Rankin Scale score. Recanalization: TIMI 2+3
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TABLE
3
CONTROLLED
STUDIES
AND
CASE
SERIES
OF
I.V.
+
I.A.
ALTEPLASE
Intervention
(dose,
mode)
Design
NIHSS
N
SICH
Recanalization
Poor
Study
or
(%)
(N,%)
outcome
author
mRS
>2
(N,(%)
22
EMS
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
alteplase
vs
RCT
-‐
35
6%
9/11
(82%)
NR
i.a.
alteplase
alone
11%
5/10
(50%)
27
Wolfe
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
alteplase
vs
Cohort
-‐
96
12%
27/41
(66%)
22/41
i.a.
alteplase
alone
(54%)
33/55
(60%)
35/55
(64%)
25
Ernst
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
Cohort
16
5%
11/16
(69%)
6/16
(38%)
alteplase
26
Suarez
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
alteplase
/
Cohort
45
0%
18/24
(67%)
5/24
(21%)
urokinase
29
Hill
I.V.
alteplase
0.9
mg/kg
followed
by
i.a.
alteplase
Cohort
6
0%
3/6
(50%)
NR
28
Shaltoni
I.V.
alteplase
0.9
mg/kg
followed
by
i.a.
Cohort
69
6%
50/69
(73%)
45%
thrombolytics
30
Burns
I.v.
alteplase
0.9
mg/kg
followed
by
i.a.
reteplase
Cohort
33
12%
24/33
(73%)
NR
w/wo
mechanical
thrombectomy
64
Keris
IA
alteplase
25mg
followed
by
i.v.
alteplase
25
mg
RCT
45
0%
6/12
(50%)
2/12(17%)
versus
no
thrombolysis
0%
NR
22/33
(67%)
65
IMS
I
I.V.
alteplase
0.6
mg/kg
followed
by
angiography
and
Cohort
80
6.3%
35/62
(56%)
46/80
endovascular
treatment
(ia
alteplase,
heparin)
when
(58%)
indicated
24
IMS
II
I.V.
alteplase
0.6
mg/kg
followed
by
angiography
and
Cohort
81
9.9%
33/55
(60%)
44/81
endovascular
treatment
(ia
alteplase,
heparin
and
i.a.
(54%)
ultrasonography
(MicroLysUS
device)
31
Sohn
I.v.
alteplase,
followed
by
i.a.
urokinase
and/or
Cohort
14
157
12.7%
NR
NR
mechanical
thrombectomy
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32
Kim
I.v.
alteplase
followed
by
urokinase
Cohort
16
18
5.6%
16/18
(89%)
9/18
(50%)
39
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38
McDougall
PENUMBRA
device
8h
18
125
102
(82%)
14
(11%)
94
(75%)
40
Zaidat
Wingspan-‐Neuroform
stents
w
8
h
18
9
8
(89%)
0
3
(33%)
or
w/o
i.a.
or
i.v.
alteplase
41
Brekenfeld
Wingspan
stents
after
failed
i.v.
8
hrs
14
12
11
(92%)
0
9
(75%)
treatment
w
or
w/o
i.v.
or
i.a.
alteplase
2
Recanalization
and
outcome
rates,
but
not
SICH
rates
were
recalculated
according
to
intent
to
treat
principle,
assuming
that
not-‐reported
patients
(i.e.
patients
without
intervention)
had
no
recanalization
and
poor
outcome.
3
In
most
studies,
patients
treated
within
3
hrs
received
i.v.
alteplase,
and
a
small
percentage
was
treated
with
i.a.
thrombolytic.
40
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0 No symptoms No symptoms
1
Symptoms,
no
Minor
symptoms
that
do
not
interfere
with
lifestyle
disability
2
Slight
disability
Slight
disability,
symptoms
that
lead
to
some
restriction
in
lifestyle,
but
do
not
interfere
with
the
patient's
capacity
to
look
after
himself.
6 Dead Death
41
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1
Penetration
The
contrast
material
passes
beyond
the
area
of
obstruction
but
fails
to
With
Minimal
opacify
the
entire
cerebral
bed
distal
to
the
obstruction
for
the
duration
of
Perfusion.
the
angiographic
run.
2
Partial
The
contrast
material
passes
the
obstruction
and
opacifies
the
arterial
bed
distal
perfusion.
to
the
obstruction.
However,
the
rate
of
entry
of
contrast
into
the
vessel
distal
to
the
obstruction
and/or
its
rate
of
clearance
from
the
distal
bed
are
perceptibly
slower
than
its
entry
into
and/or
clearance
from
comparable
areas
not
perfused
by
the
previously
occluded
vessel,
eg
the
opposite
cerebral
artery
or
the
arterial
bed
proximal
to
the
obstruction.
2a
Partial
filling
Only
partial
filling
of
the
entire
vascular
territory
is
visualized
only
2b
Slow
complete
Filling
of
all
of
the
expected
vascular
territory
is
visualized,
but
the
filling
is
filling
slower
than
normal
3
Complete
Antegrade
flow
into
the
bed
distal
to
the
obstruction
occurs
as
promptly
perfusion
as
into
the
obstruction
and
clearance
of
contrast
material
from
the
involved
bed
is
as
rapid
as
from
an
uninvolved
other
bed
of
the
same
vessel
of
the
opposite
cerebral
artery
42
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Proximal M1 2
Distal M1 2
A1
branch
1
M2 brances 1
43
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Clinical evaluation x x X x
NIHSS x x X
Laboratory x x
Neuroimaging x x X
Barthel index x X x
TICS x
EQ5D x
44
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MR
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protocol
Inclusion criteria
Exclusion criteria
Baseline
Clinical
NIHSS,
NIHSS
supplemental
motor
score,
pre-‐stroke
mRS,
blood
pressure,
GCS,
weight,
height,
body
temperature.
4
Neuro-‐imaging
parameters
will
be
assessed
by
a
central
subcommittee.
45
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protocol
Intervention
Timing
Time
of:
onset
(last
seen
well),
admission,
plain
CT,
CT
angiography,
(CTP)
start
of
i.v.
alteplase,
end
of
i.v.
alteplase,
start
of
endovascular
procedure
(needle
in
groin),
first
i.a.
bolus,
end
of
revascularization,
end
of
procedure.
Effect of intervention TICI score at start of procedure, TICI score at end of procedure
Neurological deterioration
Follow-‐up
Clinical
assessment
at
24
NIH
Stroke
Scale,
NIHS
supplemental
motor
scale,
hours
Complications
Neuro-‐imaging
at
24
Plain
CT:
location,
ASPECTS
score,
hemorrhagic
transformation
hours
(NINDS/ECASS
classification),
hyperdense
artery
sign.
Neuro
imaging
at
5-‐7
Plain
CT:
location,
ASPECTS
score,
hemorrhagic
transformation
days
(NINDS/ECASS
classification),
hyperdense
artery
sign.
Clinical
assessment
at
1
NIH
stroke
scale;
Barthel
Index;
Global
assessment
of
improvement
or
wk
or
discharge
deterioration;
clinical
complications:
hemorrhages;
Laboratory:
GFR.
Clinical assessment at 90 Modified Rankin score, NIH stroke scale, Barthel index, EQ5D, Academic
46
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47
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2010
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CLEAN
Trial
protocol
APPENDICES
COORDINATING
INVESTIGATORS
Puck
Fransen,
Dept
of
Neurology,
Erasmus
MC
Rotterdam;
JR2,
AMC
Amsterdam
(vacancy),
JR3,
Dept
of
Neurology,
UMC
Maastricht
(vacancy).
PRINCIPAL
INVESTIGATORS
Diederik
Dippel,
neurologist,
Erasmus
MC
Rotterdam,
Charles
B
Majoie,
neuroradiologist,
AMC
Amsterdam,
Yvo
Roos,
neurologist,
AMC
Amsterdam,
Robert
van
Oostenbrugge,
neurologist,
UMC
Maastricht,
Aad
van
der
Lugt,
neuroradiologist,
Erasmus
MC
Rotterdam.
LOCAL
INVESTIGATORS:
More
than
20
centers
will
join
the
pre-‐trial
phase.
A
definite
selection
of
10-‐12
centers
will
be
made
at
the
beginning
of
the
year
2010.
48
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TRIAL
STATISTICIANS
Hester
Lingsma,
methodologist,
Erasmus
MC
Rotterdam,
Ewoud
Steyerberg,
methodologist,
Erasmus
MC
Rotterdam
ADVISORY
BOARD
Peter
Koudstaal,
neurologist,
Erasmus
MC
Rotterdam,
Tommy
Andersson,
neuro
interventionist,
Karolinska
Hospital,
Stockholm,
Sweden,
Heinrich
Mattle,
neurologist,
University
hospital,
Bern,
Switzerland,
Nils
Wahlgren,
neurologist,
Karolinska
Hospital,
Stockholm,
Sweden.
49
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GENERAL
Randomization,
inclusion
in
the
trial
and
subsequent
endovascular
treatment
should
be
started
as
soon
as
possible
after
presentation
in
all
eligible
patients.
The
time-‐path
below
gives
an
indication
about
how
soon
the
following
steps
need
to
take
place.
TABLE
A1.
OPTIMAL
TIME-‐PATH
FOR
TREATMENT
AND
INCLUSION
IN
MR
CLEAN
OF
PATIENTS
WITH
ACUTE
ISCHEMIC
STROKE
AND
RELEVANT
ANTERIOR
CIRCULATION
ARTERIAL
INCLUSION
Procedure
Tx
with
i.v.
alteplase
No
tx
with
i.v.
alteplase
Randomization 60 min 30
The
selection
process
is
shown
in
Figure
3
of
the
protocol.
Three
clinical
situations
can
be
distinguished:
1
“No
response
to
i.v.
alteplase”:
in
these
patients,
there
is
no
favorable
response
to
treatment
with
intravenous
alteplase.
Vascular
neuroimaging
(CTA,
MRA,
TCD)
may
follow
treatment
with
i.v.
alteplase,
but
the
steering
committee
recommends
that
vascular
neuroimaging
is
done
at
the
start
of
i.v.
treatment.
The
exact
definition
of
favorable
response
is
left
to
the
discretion
of
the
local
investigator,
but
the
steering
committee
suggests
the
following:
neurological
recovery
to
a
level
that
would
obviate
the
indication
for
i.v.
alteplase
would
the
patient
present
with
these
symptoms.
No
minimum
time
period
between
assessment
of
the
response
to
i.v.
alteplase
and
end
of
treatment
is
required,
but
the
steering
committee
recommends
that
randomization
and
inclusion
into
the
trial,
andsubsequent
endovascular
treatment
should
be
started
as
soon
as
possible.
2
“Outside
therapeutic
window
for
i.v.
alteplase”:
these
patients
present
in
the
4.5
to
6
hour
window.
They
can
be
included
in
the
study,
and
randomized
for
endovascular
treatment
or
no
endovascular
treatment.
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3
“
Contra-‐indications
for
i.v.
alteplase”:
these
patients
have
contraindications
for
i.v.
alteplase
that
do
not
apply
to
mechanical
thrombectomy,
for
example
a
recent
cerebral
infarction
in
a
different
vascular
area,
previous
cerebral
hemorrhage,
treatment
with
coumarines
leading
with
INR
1.7
to
3.0).
They
can
be
included
in
the
study,
and
randomized
for
endovascular
treatment
or
no
endovascular
treatment.
Intra-‐arterial
thrombolysis
is
not
recommended
for
these
patients,
but
mechanical
thrombectomy
ís.
NEUROIMAGING
Neuroimaging
studies
to
assess
vessel
patency
should
preferably
be
done
before
or
simultaneously
with
treatment
with
i.v.
alteplase,
in
order
not
to
lose
time
and
brain.
Especially,
the
delay
between
end
of
i.v.
infusion
and
start
of
endovascular
treatment
should
be
minimized
to
less
than
1
hour.
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TABLE
A2-‐A:
DOSING
SCHEME
FOR
INTRAVENOUS
AND
INTRA
ARTERIAL
THROMBOLYSIS
WITH
ALTEPLASE
OR
UROKINASE
Weight
Alteplase
Alteplase
Alteplase
Alteplase
N
of
(kg)
Bolus
i.v
2/3
dose
1/3
dose
Total
i.v.
i.a.
shots
(mg)
(mg)
(mg)
dose(mg)
5
mg
alteplase
or
or
60,000
U
urokinase
50
5
25
15
45
3
55
5
28
17
50
3
60
5
31
18
54
4
65
6
34
19
59
4
70
6
36
21
63
4
75
7
38
23
68
5
80
7
41
24
72
5
85
8
43
26
77
5
90
8
46
27
81
5
95
9
48
29
86
6
100
9
51
30
90
6
>100
9
51
30
90
6
MECHANICAL
THROMBECTOMY
Randomized
clinical
trials
of
devices
for
mechanical
thrombectomy
have
not
been
done.
General
criteria
for
the
use
of
devices
in
MR
CLEAN
are
publication
of
a
case
series
at
least
20
patients
treated
with
the
device,
with
an
acceptable
rate
of
complications
and
a
TIMI
2/3
recanalization
rate
of
more
than
50%.
Currently,
two
devices
for
mechanical
thrombectomy
(MERCI
and
PENUMBRA),
specifically
designed
for
treatment
of
acute
intracranial
arterial
occlusions
have
been
evaluated
in
case
series,
and
have
been
FDA
approved
for
this
purpose.
One
catheter
system,
EKossonics
SV,
designed
for
delivery
of
ultrasound-‐waves
to
the
occluding
thrombus,
has
been
evaluated
in
IMS2
and
will
be
evaluated
together
with
the
MERCI
system
in
IMS3.
These
devices
have
been
shown
to
be
capable
of
recanalization,
with
an
acceptable
rate
of
complications.39
Therefore,
Currently
the
MERCI,
Penumbra,
Solitaire
and
Ekossonics
SV
devices
fulfill
the
requirements
as
formulated
by
the
steering
committee
(Table
A3).
Two
stent
devices
have
been
approved
for
intracranial
treatment,
but
not
for
treatment
of
patients
with
acute
ischemic
stroke,
moreover
published
experience
with
treatment
is
limited.
The
steering
committee
of
MR
CLEAN
will
be
actively
seeking
evidence
that
will
make
specific
stenting
devices
acceptable
for
use
in
the
trial.
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TABLE
A3.
LIST
OF
MECHANICAL
THROMBECTOMY
DEVICES
THAT
ARE
AVAILABLE
IN
THE
NETHERLANDS,
THEIR
MODE
OF
ACTION
AND
CURRENT
STATUS.
6
Device
Mode
of
action
5
Manufacturer
NL
Dealer
Approval Evaluation
7
studies
Allowed
Merci
retriever
R,A
Concentric
Medical
Top
Medical
FDA
CS
Penumbra
System
A,F
Penumbra
Incm
US
Penumbra
FDA
CS
Solitaire
Stent
(ev3)
S
EV3
Ev3
CE
CS
EKossonic
SV
U
EKOS
Bothell
Wash
Angiocare
CE
CR
Pending
8
Wingspan
stent
A
Boston
Scientific
Boston
sci
FDA
CS
CATCH
device
R,A
Balt
Extrusion
Angiocare
CE
CR
Revasc
S
Micrus
Angiocare
CE
?
Moses
S
Micrus
Angiocare
CE
?
Fast
A
Micrus
Angiocare
CE
?
Vasco+35ASPI
A
Balt
Angiocare
CE
?
5
R=retraction,
A=aspiration,
S=Stenting,
F=Fragmentation,
U=
ultrasound
enhanced
lysis
6
FDA
=
Federal
Drugs
Agency,
CE
=
Conformité
Européenne,
which
means
in
concordance
with
European
legislation.
7
U=unpublished
studies
only,
CR=case
reports,
CS=case
series
8
Approved
only
for
elective
treatment
of
intracranial
stenosis.
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WHEN
1)
The
pre-‐intervention
angiogram
should
be
performed
via
the
guiding
catheter
to
evaluate
the
site
of
vessel
occlusion,
extent
of
thrombus,
territories
involved,
concomittant
pathologies
and
to
assess
collateral
flow.
45
2)
After
passing
the
occlusion
site
a
microcatheter
injection
should
be
performed
to
assess
the
distal
vascular
bed.
3)
After
each
bolus
of
thrombolytic
agent
a
control
angiogram
via
a
microcatheter
injection
and/or
guiding
catheter
injection
should
be
performed
to
assess
vessel
patency.
4)
After
each
passage
of
a
mechanical
device,
a
control
angiogram
should
be
performed
via
the
guiding
catheter
to
assess
vessel
patency.
5)
At
the
end
of
the
procedure
the
angiogram
should
be
repeated
via
the
guiding
catheter
to
assess
the
final
angiographic
outcome
HOW
The
angiogram
should
include
the
internal
carotid
artery
(or
common
carotid
in
case
of
occlusion
or
severe
stenosis
of
internal
carotid)
feeding
the
target
vessel
as
demonstrated
on
CTA.
To
completely
assess
the
collateral
circulation,
injections
of
the
contralateral
internal
carotid
artery
(or
common
carotid
in
case
of
occlusion
or
severe
stenosis
of
internal)
and
the
dominant
vertebral
artery
are
preferred.
However,
they
are
not
necessary
for
inclusion
in
the
study.
AP
views
and
lateral
views
of
the
intracranial
arteries
are
obtained.
It
is
essential
that
the
angiograms
include
both
the
arterial
and
venous
phases
of
the
injection
to
evaluate
the
collateral
pathways
and
perfusion
of
the
distal
vascular
bed.
The
angiograms
should
be
performed
via
the
guiding
catheter
with
the
same
catheter
position,
contrast
injection
volume
and
rate
(6-‐8ml
with
4ml/s
for
internal
carotid,
8-‐10ml
with
4-‐6ml/s
for
common
carotid
and
6-‐8ml
with
4-‐5ml/s
for
vertebral
artery),
and
angiographic
views
before,
after
the
procedures
to
adequately
assess
the
results
of
therapy.
2. After
passing
the
occlusion
site,
after
each
bolus
of
thrombolytic
agent
and
after
each
pass
of
a
mechanical
device:
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FIGURES
55
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FIGURE
2
Assumed
distribution
of
the
primary
outcome,
according
to
the
modified
Rankin
scale
in
group
receiving
no
intra-‐arterial
treatment
(mRS-‐C)
(control)
and
the
group
receiving
intra-‐
arterial
treatment
(mRS-‐I).
THe
cumulative
proportion
of
patients
in
mRS
0-‐3
has
increased
with
10%.
30%
25%
20%
proportion
15%
mRS_C
mRS_I
10%
5%
0%
0
1
2
3
4
5
6
mRS
score
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FIGURE 3. RANDOMIZATION AND INCLUSION OF PATIENTS IN THE TRIAL
57
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58
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3.5
June
11
,
2014
MR
CLEAN
Trial
protocol
MR
CLEAN-‐Multicenter
Randomized
Clinical
trial
of
Endovascular
treatment
for
Acute
ischemic
stroke
in
the
Netherlands.
Protocol
ID
NTR1804
/
ISRCTN10888758
Version 3.5
Coordinating
investigator
and
executive
Diederik
WJ
Dippel,
neurologist
Erasmus
MC
University
Medical
Center
Rotterdam,
PO
Box
2040
committee
of
the
trial
3000
CA
Rotterdam,
The
Netherlands.
T
+31
10
7043979;
F
+31
10
7044721
E
d.dippel@erasmusmc.nl.
Yvo
B
Roos,
neurologist
AMC
Amsterdam
Charles
Majoie,
radiologist,
AMC
Amsterdam
Aad
van
der
Lugt,
radiologist,
Erasmus
MC
Rotterdam
Robert
van
Oostenbrugge,
neurologist,
Maastricht
UMC
Wim
van
Zwam,
radiologist,
Maastricht
UMC
Sponsor
Raad
van
Bestuur
Erasmus
MC
University
Medical
Center
Rotterdam.
59
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CLEAN
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protocol
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CLEAN
Trial
protocol
Diederik
W
Dippel,
Charles
B
Majoie,3
Aad
van
der
Lugt,2
Wim
van
Zwam5
Robert
J
van
Oostenbrugge,6
Puck
Fransen,1,2
Debbie
Beumer,1,6
Olvert
A
Berkhemer,1,3
Lucie
A
van
den
Berg4
and
Yvo
B
Roos4
for
the
MR
CLEAN
investigators.*
Departments
of
Neurology1
and
Radiology2
of
Erasmus
MC
University
Medical
Center
Rotterdam,
Radiology3
and
Neurology4
of
the
Academisch
Medisch
Centrum,
Amsterdam,
The
Netherlands,
and
Radiology5
and
Neurology6
of
the
Maastricht
University
Medical
Center,
The
Netherlands.
*
The
MR
CLEAN
investigators
are
listed
in
the
appendix.
Correspondence:
Diederik
WJ
Dippel,
Dept
of
Neurology,
Erasmus
MC
University
Medical
Center
Rotterdam,
PO
Box
2040
3000
CA
Roterdam,
The
Netherlands.
T
+31
10
7043979;
F
+31
10
7044721
E
d.dippel@erasmusmc.nl.
Original
protocol
:
Version
3.0,
date
February
20,
2010
Amendment
1:Version
3.1,
date
March
6
,2012
Amendment
2
:Version
3.2,
date
December
12,
2012
Amendment
3:Version
:
3.3,
date
February
26,
2013
Amendment
4:Version
3.4,
date
September
5,
2013
Amendment
5:Version
3.5,
date
June
11,
2014
62
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CLEAN
Trial
protocol
Acknowledgments
.............................................................................................................................................................................................................
12
1.4 Needed: a randomized clinical trial of endovascular treatment in acute ischemic stroke .......................................................... 16
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Table 2: randomized clinical trials of intra-‐arterial thrombolysis ................................................................................................................. 37
Table 3 controlled studies and case series of i.v. + i.a. alteplase ................................................................................................................. 38
Table 4 studies of mechanical treatment in acute ischemic stroke ............................................................................................................ 40
Table
5B.
Thrombolysis
in
Cerebral
Infarction
(TICI)
scale.
.........................................................................................................................
42
45
Table
5C
Clot
burden
score
for
CTA
and
MRA
.................................................................................................................................................
43
46
Appendix
3
Recommendations
of
the
Steering
committee
with
regard
to
endovascular
treatment
procedures,
thrombolytic
agents,
and
type
of
mechanical
thrombectomy.
...............................................................................................................................................
50
Table
A1.
Optimal
Time-‐path
for
treatment
and
inclusion
in
MR
CLEAN
of
patients
with
acute
ischemic
stroke
and
relevant
anterior
circulation
arterial
inclusion
.....................................................................................................................................................................
50
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase .................................. 52
Table
A3.
List
of
mechanical
thrombectomy
devices
that
are
available
in
The
Netherlands,
their
mode
of
action
and
current
status.
................................................................................................................................................................................................................................
53
Figure 3. Randomization and inclusion of patients in the trial ...................................................................................................................... 57
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1.4 Needed: a randomized clinical trial of endovascular treatment in acute ischemic stroke .......................................................... 73
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Table 2: randomized clinical trials of intra-‐arterial thrombolysis ................................................................................................................. 92
Table 3 controlled studies and case series of i.v. + i.a. alteplase ................................................................................................................. 93
Table 4 studies of mechanical treatment in acute ischemic stroke ............................................................................................................ 94
Table
5B.
modifed
Thrombolysis
in
Cerebral
Infarction
(TICI)
scale.
.......................................................................................................
95
45
Table
5C
Clot
burden
score
for
CTA
and
MRA
.................................................................................................................................................
96
46
Appendix
3
Recommendations
of
the
Steering
committee
with
regard
to
endovascular
treatment
procedures,
thrombolytic
agents,
and
type
of
mechanical
thrombectomy.
.............................................................................................................................................
102
Table
A1.
Optimal
Time-‐path
for
treatment
and
inclusion
in
MR
CLEAN
of
patients
with
acute
ischemic
stroke
and
relevant
anterior
circulation
arterial
inclusion
...................................................................................................................................................................
102
Table A2-‐a: dosing scheme for intravenous and intra arterial thrombolysis with alteplase OR Urokinase ................................ 104
Table
A3.
List
of
mechanical
thrombectomy
devices
that
are
available
in
The
Netherlands,
their
mode
of
action
and
current
status.
..............................................................................................................................................................................................................................
105
APPENDIX 5: Protocol amendment MR CLEAN trial; substantial Protocol 3.1. ..................................................................................... 106
APPENDIX 6 : PROTCOL AMENDMENT MR CLEAN TRIAL SUBSTANTIAL PROTOCOL 3.2 .................................................................... 107
Appendix 7: PROTCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.3 ..................................................................... 108
Appendix 8: PROToCOL AMENDMENT MR CLEAN TRIAL; SUBSTANTIAL PROTOCOL 3.4 .................................................................. 110
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Appendix 9: PROToCOL AMENDMENT MR CLEAN TRIAL; PROTOCOL 3.5 .............................................................................................. 110
Time path of the analyses and locking of the database. .................................................................................................................................... 116
Figure 3. Randomization and inclusion of patients in the trial .................................................................................................................... 120
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Time path of the analyses and locking of the database. .................................................................................................................................... 126
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ACKNOWLEDGMENTS
MR
CLEAN
is
partly
funded
by
the
Netherlands
Heart
Foundation
(2008T030),
and
by
unrestricted
grants
from
AngioCare
BV,
EV3®,
MEDAC
Gmbh/LAMEPRO,
Penumbra
Inc
and
Concentric
Medical
/TOP
Medical
BV.
The
study
is
designed,
and
will
be
conducted,
analyzed,
and
interpreted
by
the
investigators
independently
of
all
sponsors.
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SUMMARY
DESIGN
MR
CLEAN
is
a
pragmatic
phase
III
multicenter
randomized
clinical
trial
with
blinded
outcome
assessment.
The
intervention
contrast
is
intra-‐arterial
treatment
versus
no
intra-‐
arterial
treatment.
STUDY
POPULATION
Patients
should
have
a
clinical
diagnosis
of
acute
ischemic
stroke,
MRI9
or
CT
ruling
out
intracerebral
hemorrhage,
a
score
on
the
National
Institutes
of
Health
Stroke
Scale
(NIHSS)
of
2
points
or
more,
a
relevant
intracranial
arterial
occlusion,
demonstrated
by
neuro-‐
imaging
and
the
possibility
to
start
endovascular
treatment
within
6
hours
after
stroke
onset.
INTERVENTION
Endovascular
treatment
may
consist
of
intra-‐arterial
thrombolysis
with
urokinase
or
alteplase,
mechanical
treatment
or
both.
Mechanical
treatment
refers
to
retraction
or
aspiration
of
the
thrombus
with
a
catheter
guided
device,
or
stenting.
The
exact
choice
of
endovascular
treatment
modality
for
each
patient
is
left
to
the
discretion
of
the
local
investigator
and
treating
physicians.
The
steering
committee
will
provide
recommendations
and
guidelines
for
treatment
and
selection
of
patients
in
the
study.
Background
medical
management
is
delivered
according
to
national
standards
and
guidelines.
It
may
include
intravenous
alteplase
within
the
first
4.5
hours
after
onset.
9
All
abbreviations
are
listed
in
Table
1.
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DISCUSSION
MR
CLEAN
is
a
pragmatic
trial.
Inclusion
of
patients
will
take
4
years,
and
starts
early
in
2010.
Key
words:
alteplase,
endovascular
treatment,
acute
ischemic
stroke,
randomized
controlled
trial
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CLEAN
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effect
was
not
statistically
significant.19
Several
non-‐randomized
studies
with
historical
controls,20
or
controls
in
other
centers,21
suggested
a
benefit
of
intra-‐arterial
thrombolysis.
1.4
NEEDED:
A
RANDOMIZED
CLINICAL
TRIAL
OF
ENDOVASCULAR
TREATMENT
IN
ACUTE
ISCHEMIC
STROKE
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We
conclude
from
this
overview
that
intra-‐arterial
treatment,
either
with
a
thrombolytic
agent
or
by
mechanical
means
is
able
to
recanalize
acutely
occluded
cerebral
arteries
in
selected
patients,
within
reasonable
safety
margins.
Whether
this
is
the
case
in
an
unselected
sample
of
patients
with
acute
ischemic
stroke
caused
by
occlusion
is
likely,
but
unproven.
A
randomized
clinical
trial
addressing
the
question
whether
intra-‐arterial
treatment
improves
neurological
outcome
in
patients
with
a
relevant
occlusion
in
the
intracranial
proximal
anterior
circulation
is
therefore
needed.
For
the
trial
results
to
be
generalizable
and
representative
of
what
is
state
of
the
art
approach
in
intra-‐arterial
treatment,
the
trial
design
should
accommodate
the
possibility
to
use
local
fibrinolytics
and
or
mechanical
thrombectomy
devices,
for
a
broad
range
of
patients
with
acute
ischemic
stroke
caused
by
a
proximal
thrombo-‐embolic
occlusion
of
one
of
the
intracranial
arteries
belonging
to
the
anterior
circulation.
Important
subgroups
to
whom
this
question
of
effectiveness
and
safety
applies
are
patients
who
have
been
treated
unsuccessfully
with
intravenous
thrombolysis,
patients
who
can
be
treated
within
6
hours,
but
do
not
meet
the
time-‐window
requirements
for
intravenous
thrombolysis,
and
patients
with
contra-‐indications
for
intravenous
and/or
intra-‐arterial
thrombolytic
treatment
(thrombectomy
only).
To
answer
this
question,
we
initiated
a
large
multicenter
pragmatic
trial
of
intra-‐arterial
treatment
(by
means
of
alteplase
and
or
mechanical
treatment)
versus
standard
medical
treatment,
in
patients
with
acute
ischemic
stroke
of
less
than
6
hours
of
onset,
the
MR
CLEAN
study.
The
trial
applies
the
grey
area
principle:
when
a
patient’s
clinical
profile
meets
inclusion
and
exclusion
criteria,
and
according
to
investigator
and
treating
physician
there
is
sufficient
uncertainty
concerning
the
question
whether
the
patient
should
receive
intra-‐arterial
treatment,
the
patient
is
eligible
for
inclusion
in
the
trial.
2.
OBJECTIVES
The
primary
objective
of
this
study
is
to
estimate
the
effect
of
endovascular
treatment
on
overall
functional
outcome
after
acute
ischemic
stroke
of
less
than
six
hour
duration,
in
patients
with
a
symptomatic
occlusion.
The
secondary
objectives
are
to
assess
the
safety
of
endovascular
treatment
with
regard
to
the
occurrence
of
hemorrhagic
and
ischemic
complications,
the
efficacy
with
regard
to
obtaining
recanalization,
and
to
evaluate
predictors
of
recanalization,
including
imaging
aspects
and
hemostatic
parameters.
Moreover,
we
want
to
assess
the
safety
and
efficacy
of
different
types
of
endovascular
treatment
(i.e.
mechanical
treatment,
intra-‐arterial
thrombolysis)
different
combinations
of
treatment
(i.e.
with
intravenous
alteplase)
and
different
timings
of
treatment.
Tertiary
objectives
are
to
carry
out
case
studies
of
implementation
strategies
and
loco-‐regional
solutions
for
barriers
to
the
delivery
of
endovascular
treatment
for
acute
ischemic
stroke
and
to
collect
data
for
cost-‐effectiveness
analysis
of
endovascular
treatment
compared
with
standard
treatment.
3.
STUDY
DESIGN
This
is
a
multicenter
clinical
trial
with
randomized
treatment
allocation,
open
label
treatment
and
blinded
endpoint
evaluation
(PROBE
design).
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The
intervention
contrast
is
endovascular
treatment
(alteplase
or
urokinase,
and/or
mechanical
treatment)
versus
no
endovascular
treatment.
The
treatment
is
provided
in
addition
to
best
medical
management,
including
intravenous
thrombolysis.
The
study
will
run
in
at
least
10
large
hospitals
in
the
Netherlands
for
a
period
of
five
years
(4
years
of
patient
inclusion),
and
starts
in
2010.
4. STUDY POPULATION
4.1
POPULATION
Patients
over
18
years
old,
with
acute
ischemic
stroke,
a
symptomatic
anterior
proximal
artery
occlusion
which
can
be
treated
within
6
hours
after
stroke
onset
are
eligible
for
participation
in
this
trial.
INCLUSION
CRITERIA
• A
clinical
diagnosis
of
acute
stroke,
with
a
deficit
on
the
NIH
stroke
scale
of
2
points
or
more.
• CT
or
MRI
scan
ruling
out
intracranial
hemorrhage.
• Intracranial
arterial
occlusion
of
the
distal
intracranial
carotid
artery
or
middle
(M1/M2)
or
anterior
(A1/A2)
cerebral
artery,
demonstrated
with
CTA,
MRA
or
DSA.
• The
possibility
to
start
treatment
within
6
hours
from
onset.
• Informed
consent
given.
• Age
18
or
over.
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• Clinical
or
laboratory
evidence
of
coagulation
abnormalities,
i.e.
platelet
count
<90
x
10 /L,
APTT>50
sec
or
INR
>1.7.
Current
treatment
with
oral
thrombin
antagonists,
such
as
argatroban
and
dabigatran
or
treatment
with
oral
selective
Factor
Xa
inhibitors,
such
as
rivaroxaban.
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patient
will
be
assigned
to
the
standard
arm
and
will
remain
at
the
randomization
center.
Follow
up
will
be
monitored
in
this
center
until
discharge.
10
10
One
of
the
randomization
centers
(Reinier
de
Graaf)
has
the
available
resources
to
treat
patients
with
intra-‐arterial
therapy
(equipment
and
supporting
staff)
but
there
is
a
shortage
of
neurointerventionalist.
Instead
of
transferring
the
patient
to
the
closest
MR
CLEAN
center
(HAGA)
the
members
of
the
neurointerventional
team
will
visit
the
Reinier
de
Graaf
hospital.
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allowance
into
the
trial
of
a
particular
device.
Proposals
will
be
prepared
by
the
executive
committee,
and
should
be
approved
by
a
majority
of
the
steering
committee.
6.METHODS
PRIMARY
OUTCOME
The
primary
outcome
is
the
score
on
the
modified
Rankin
scale
at
90
days
(Table
5a).
SECONDARY OUTCOMES
IMAGING PARAMETERS
• Vessel
recanalization
at
24
hours
after
treatment,
assessed
by
CTA
or
MRA.
The
criteria
for
recanalization
on
CTA
or
MRA
are
based
on
the
Arterial
Occlusive
Lesion
(AOL)
scale,
and
the
Clot
46
Burden
Score,
proposed
by
Puetz
et
al
(Table
5c) .
• Infarct
size
assessed
by
CT
on
day
5-‐7,
using
standard
methods,
including
manual
tracing
of
the
infarct
47,
48
perimeter
and
semi-‐automated
pixel
thresholding.
Infarct
size
at
day
5-‐7
will
be
compared
with
plain
CT
and
perfusion
CT
results
(if
available)
at
baseline.
• CTA
or
MRA
at
24
hours
will
be
compared
with
baseline
vessel
imaging
data,
to
estimate
the
recanalization
rate.
Perfusion
CT
at
baseline
is
optional,
but
available
at
most
centers.
Clinical
parameters
CLINICAL PARAMETERS
• NIHSS 49, including NIH supplemental motor score,50 at 24 hours.
FUNCTIONAL OUTCOME
SAFETY
PARAMETERS
Safety
is
an
issue
of
concern,
as
the
experience
with
the
intervention,
overall,
and
within
the
participating
centers,
is
limited.
Safety
parameters
include
hemorrhagic
complications,
and
short
term
outcome
(mortality,
Barthel
index
and
NIHSS
at
24
hours
and
at
one
week
or
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discharge).
As
we
will
make
use
of
web-‐based
data-‐entry,
these
data
will
be
available
on
short
notice.
The
primary
safety
parameter
will
be
neurologic
deterioration
within
24
hours
from
inclusion
in
the
study.
Neurological
deterioration
is
defined
as
any
decline
in
NIHSS
of
more
4
points
or
more.
In
these
patients,
urgent
brain
CT
is
mandatory.
This
serious
adverse
event
will
be
further
classified
as
due
to
intracranial
hemorrhage,
ischemia
or
other
(undetermined)
cause.
A
full
list
of
serious
adverse
events
is
provided
in
section
7.1
Adverse
events.
If
the
local
investigator
or
other
member
of
the
team
at
a
trial
centre
has
a
concern
about
the
outcome
of
their
trial
procedures,
they
should
inform
the
MR
CLEAN
trial
office,
which
will
organize
a
blinded
assessment
of
the
relevant
outcome
events.
This
will
be
submitted
by
the
central
office
to
the
chairman
of
the
data
monitoring
committee,
who
may
recommend
further
action,
such
as
suspending
randomization
at
the
centre.
Similarly,
the
database
manager
at
the
trial
office
will
monitor
outcome
events
and
if
there
are
three
consecutive
deaths
or
three
consecutive
serious
adverse
events
at
a
single
centre
within
30
days
of
treatment
in
the
same
arm
of
the
study,
then
assessment
of
the
events
will
be
triggered.
A
cumulative
death
rate
of
more
than
50%
or
a
cumulative
serious
adverse
event
rate
exceeding
20%
over
10
cases
during
hospital
admission
would
also
trigger
careful
assessment
of
the
relevant
outcome
events.
6.2
RANDOMIZATION
The
randomization
procedure
will
be
computer-‐
and
web-‐based,
using
permuted
blocks.
Back-‐up
by
telephone
will
be
provided.
Randomization
is
allowed
when
the
occlusion
has
been
established
by
CTA,
MRA,
DSA
or
TCD.
Selection
of
patients
for
randomization
follows
the
grey
area
principle.
Randomization
will
be
stratified
for
center,
use
of
intravenous
alteplase,
planned
treatment
modality
(mechanical
thrombectomy
or
not)
and
stroke
severity,
(NIHSS
>14
or
not).
Patients
with
contra-‐indications
for
intravenous
thrombolysis
are
allowed
into
the
trial.
This
concerns
patients
who
cannot
be
treated
within
4.5
hours
from
onset,
but
only
in
the
4.5
to
6
hour
interval,
and
patients
with
either
major
surgery,
gastrointestinal
bleeding
or
urinary
tract
bleeding
within
the
previous
2
weeks,
or
arterial
puncture
at
a
non-‐compressible
site
within
the
previous
7
days.
Patients
with
exclusion
criteria
for
intra-‐arterial
thrombolysis
are
also
allowed
into
the
trial.
They
can
be
included
and
randomized
for
endovascular
treatment
or
no
endovascular
treatment.
Treatment
with
mechanical
thrombectomy
is
allowed,
but
intra-‐arterial
thrombolysis
is
not
allowed
in
these
patients.
The
treating
physicians
are
free
to
change
the
actual
mode
of
treatment
during
the
procedure,
as
long
as
they
comply
with
the
treatment-‐
specific
exclusion
criteria
and
recommended
devices.
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6.3
BLINDING
It
will
not
be
possible
to
view
the
treatment
allocation
before
the
patient
is
registered
in
the
study
database,
nor
will
it
be
possible
to
remove
the
patient
from
the
study
base
after
treatment
assignment
has
become
known.
Both
patient
and
treating
physician
will
be
aware
of
the
treatment
assignment.
Information
on
outcome
at
three
months
will
be
assessed
through
standardized
forms
and
procedures.
Assessment
of
outcome
on
the
modified
Rankin
scale
will
be
based
on
this
information,
by
assessors
who
are
blind
to
the
treatment
allocation.
Results
of
neuroimaging
will
be
also
assessed
in
a
blinded
manner.
Information
on
treatment
allocation
will
be
kept
separate
from
the
main
study
database.
The
steering
committee
will
be
kept
unaware
of
the
results
of
interim
analyses
of
efficacy
and
safety.
The
trial
statistician
will
combine
data
on
treatment
allocation
with
the
clinical
data
in
order
to
report
to
the
data
monitoring
committee
(DMC).
FOLLOW-‐UP
DATA
At
24
hours,
a
clinical
examination
including
NIH
stroke
scale
assessment
will
be
carried
out.
Also,
all
patients
will
undergo
CTA
or
MRA
imaging.
At
day
5-‐7
all
patients
will
undergo
CT
or
MRI.
Raw
data
will
be
forwarded
to
the
trial
office
for
blind
evaluation.
At
1
week,
clinical
status,
NIH
stroke
scale
score
and
adverse
events
will
be
reported
as
well
as
discharge
destination,
in
order
to
enable
the
trial
office
to
conduct
the
final
3-‐month
follow-‐up
by
telephone
interview.
The
standardized
telephone
interview
will
include
a
short
questionnaire
based
on
the
three
simple
questions,
assessment
of
modified
Rankin
Scale,
Barthel
Index,
and
Euroqol5D.51-‐53,
60-‐
62
.
WITHDRAWAL
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Patients
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
or
stop
the
allocated
intervention
for
urgent
medical
reasons.
Every
attempt
will
be
made
to
complete
follow-‐up
in
these
patients.
7.SAFETY REPORTING.
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interim
analyses
of
mortality
and
of
any
other
information
that
is
available
on
major
endpoints
(including
serious
adverse
events
believed
to
be
due
to
treatment)
will
be
supplied,
in
strict
confidence,
to
the
chairman
of
the
Data
Monitoring
Committee,
along
with
any
other
analyses
that
the
Committee
may
request.
In
the
light
of
these
analyses,
the
Data
Monitoring
Committee
will
advise
the
chairman
of
the
Steering
Committee
if,
in
their
view,
the
randomized
comparisons
in
MR
CLEAN
have
provided
both
(i)
"proof
beyond
reasonable
doubt"
that
for
all,
or
for
some
specific
types
of
patients,
one
particular
treatment
is
clearly
indicated
or
clearly
contraindicated
in
terms
of
a
net
difference
in
outcome,
and
(ii)
evidence
that
might
reasonably
be
expected
to
influence
materially
patient
management.
Appropriate
criteria
of
proof
beyond
reasonable
doubt
cannot
be
specified
precisely,
but
a
difference
of
at
least
3
standard
deviations
in
an
interim
analysis
of
a
major
endpoint
may
be
needed
to
justify
halting,
or
modifying,
the
study
prematurely.
This
criterion
has
the
practical
advantage
that
the
number
of
interim
analyses
is
of
little
importance.
8.
STATISTICAL
ANALYSES
Baseline
characteristics
will
be
summarized
by
means
of
simple
descriptive
statistics.
The
main
analysis
of
this
trial
consists
of
a
single
comparison
between
the
trial
treatment
groups
of
the
primary
outcome
after
90
days.
The
analysis
will
be
based
on
the
intention-‐to-‐treat
principle.
The
primary
effect
parameter
should
take
the
whole
range
of
the
modified
Rankin
scale
(mRS)
into
account
and
is
defined
as
the
relative
risk
for
improvement
on
the
mRS
estimated
as
an
odds
ratio
with
ordinal
logistic
regression.63
Multivariable
regression
analysis
will
be
used
to
adjust
for
chance
imbalances
in
main
prognostic
variables
between
intervention
and
control
group,
such
as
age,
stroke
severity
(NIHSS),
time
since
onset,
previous
stroke,
atrial
fibrillation
and
diabetes
mellitus.
Secondary
effect
parameters
will
be
the
improvement
according
to
the
classical
dichotomizations
of
the
modified
Rankin
scale
at
0-‐1
vs
2-‐6
and
0-‐2
vs
3-‐6,
the
presence
of
vessel
patency
on
CTA,
MRA
or
DSA
at
24
hours,
and
the
score
on
the
NIHSS
at
24
hours
and
1
week
or
discharge.
With
regard
to
the
range
of
secondary
outcome
parameters
we
will
use
simple
2x2
tables,
two-‐group
t-‐tests,
Mann-‐Whitney
tests,
and
multivariable
linear
and
logistic
regression
models,
where
appropriate.
In
all
analyses,
statistical
uncertainty
will
be
quantified
by
means
of
95%
confidence
intervals.
Subgroup
analyses
will
be
carried
out
to
estimate
the
effect
intra-‐arterial
thrombolysis,
mechanical
treatment
and
combination
therapy.
Although
the
size
of
this
study
will
not
allow
for
precise
estimates
of
treatment
effect
in
subgroups,
we
will
assess
heterogeneity
of
effects,
and
analyze
consistency
of
effects
on
secondary
outcomes.
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Written
informed
consent
will
be
obtained
from
all
patients
and
a
copy
must
be
retained
by
the
randomizing
centre.
All
patients
will
be
provided
with
a
written
explanation
of
the
study.
Because
of
the
urgent
character
of
the
treatment
informed
consent
is
subdivided
in
an
informed
consent
form
with
a
short
description
of
the
procedure
for
immediate
use,
and
an
extensive
version
which
will
be
discussed
with
the
patient
after
the
procedure.
After
approval
by
the
patient
or
his/her
legal
representative,
the
patient’s
treating
physician
will
inform
a
study
physician
of
the
presence
of
a
patient
with
acute
ischemic
stroke
who
is
potentially
eligible
for
the
present
study.
The
study
physician
will
inform
the
patient
orally
and
in
writing
and
will
obtain
his/her
written
informed
consent.
In
case
the
patient
is
legally
incompetent,
for
example
because
of
aphasia
or
anosognosia,
written
informed
consent
will
be
obtained
from
a
legal
representative.
Because
the
study
physicians
are
also
involved
in
the
clinical
care
of
patients
with
acute
ischemic
stroke,
it
appears
inevitable
that
in
some
occasions
the
study
physician
will
also
be
the
patient’s
treating
physician.
As
this
is
an
acute
stroke
trial
with
a
narrow
time
window
for
the
start
of
treatment,
and
because
of
time-‐consuming
study-‐related
procedures
after
informed
consent
will
be
obtained,
the
time
for
consideration
of
participation
in
the
trial
will
be
limited
to
the
first
few
hours
after
stroke
onset.
Even
within
this
time
frame,
a
decision
on
participation
should
preferably
be
taken
as
soon
as
possible,
at
least
within
30
minutes.
Especially
patients
with
large
cortical
infarcts
may
not
be
able
to
judge
the
pros
and
cons
of
participation
in
the
trial
sufficiently,
most
often
because
of
aphasia.
As
aphasia
is
present
in
approximately
25%
of
the
patients
with
acute
stroke
and
because
patients
with
large
cortical
infarcts
may
benefit
most
from
intra-‐arterial
treatment
on
theoretical
grounds,
it
may
be
considered
inappropriate
to
exclude
these
patients
from
the
trial.
Incapacitated
patients
in
the
control
group
are
treated
according
to
current
standards
and
participation
in
the
trial
does
therefore
not
carry
a
risk;
the
burden
caused
by
the
additional
investigations
is
considered
minimal.
10.1
PRIVACY
All
included
patients
will
be
assigned
a
unique
number.
Name
and
address
will
be
stored
separately
from
the
study
data.
Consent
with
participation
in
the
study
will
be
asked
from
all
83
Version
3.5
June
11
,
2014
MR
CLEAN
Trial
protocol
patients
after
presenting
them
with
standard
written
forms.
The
information
describes
the
purpose
of
the
study,
interventions,
potential
hazards
and
benefits
and
the
procedures
for
recording
of
clinical
information
and
three
month
follow
up.
10.2
SUBSTUDIES
Substudies
will
be
carried
out
on
the
role
of
hemostatic
factors
as
effect
modifiers
in
endovascular
treatment
(van
Oostenbrugge).
The
hematological
substudy
is
called:
SMARTIS
(the
study
of
haemostatic
markers
in
intra
arterial
treatment
for
acute
ischemic
stroke).
We
refer
to
a
separate
study
protocol
for
this.
A
second
substudy
will
be
carried
out
to
investigate
the
role
of
MRI
(DWI
sequence).
This
sequence
is
conducted
to
identify
the
infarct
core
(see
separate
substudy
protocol:
DIANE;
(“Value
of
Diffusion-‐Weighted
MRI
for
Selection
of
Patients
for
IA
Treatment
for
Acute
Ischemic
Stroke
in
the
NEtherlands”).
Furthermore
we
will
carry
out
a
third
substudy
on
long
term
follow-‐up
and
cost-‐
effectiveness
of
endovascular
treatment
(Roos)
.
For
this
study
the
follow-‐up
will
be
extended
to
two
years.
We
refer
to
a
separate
substudy
protocol
for
a
detailed
description
(
‘CLOT-‐MR
CLEAN:
Cost-‐effectiveness
analyses
and
LOng
Term
follow-‐up
in
patients
randomised
in
a
multicenter
randomized
clinical
trial
of
endovascular
treatment
for
acute
ischemic
stroke
in
The
Netherlands’).
A
substudy
on
clinical
and
radiological
predictors
of
recanalization
(Majoie)
and
functional
outcome
after
treatment
(Dippel)
as
well
as
interobserver
and
validation
studies
of
rapid
reperfusion
scores
will
be
carried
out.
The
MR
CLEAN
investigators
share
a
positive
attitude
towards
the
conductance
of
substudies
in
general.
Proposals
for
substudies
will
be
discussed
within
the
executive
committee
and
decisions
will
be
made
by
the
steering
committee.
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R.
The
Academic
Medical
Center
Linear
Disability
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item
bank:
item
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Qual
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29;3:83.:83.
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Validity
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Cognitive
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Validation
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based
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impairment
and
dementia.
BMC
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2005;5(1):8.
89
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11
,
2014
MR
CLEAN
Trial
protocol
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RO,
Geda
YE,
Pankratz
VS,
Christianson
TJ,
Petersen
RC,
Rocca
WA.
Validation
of
the
Telephone
Interview
for
Cognitive
Status-‐modified
in
Subjects
with
Normal
Cognition,
Mild
Cognitive
Impairment,
or
Dementia.
Neuroepidemiology
2009
November
5;34(1):34-‐42.
(58)
Murray
CJ,
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A,
Baltussen
RM.
Development
of
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generalized
cost-‐effectiveness
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Health
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Standardisation
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in
economic
evaluations.
Pharmacoeconomics
2002;20(7):443-‐54.
(60)
Berge
E,
Fjaertoft
H,
Indredavik
B,
Sandset
PM.
Validity
and
reliability
of
simple
questions
in
assessing
short-‐
and
long-‐term
outcome
in
Norwegian
stroke
patients.
Cerebrovasc
Dis
2001;11(4):305-‐10.
(61)
Dorman
P,
Dennis
M,
Sandercock
P.
Are
the
modified
"simple
questions"
a
valid
and
reliable
measure
of
health
related
quality
of
life
after
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United
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Collaborators
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International
Stroke
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J
Neurol
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2000
October;69(4):487-‐93.
(62)
van
Swieten
JC,
Koudstaal
PJ,
Visser
MC,
Schouten
HJ,
van
GJ.
Interobserver
agreement
for
the
assessment
of
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in
stroke
patients.
Stroke
1988
May;19(5):604-‐7.
(63)
Murray
GD,
Barer
D,
Choi
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H,
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B,
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GS,
Teasdale
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Weir
CJ.
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the
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the
sliding
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2005
May;22(5):511-‐7.
(64)
Keris
V,
Rudnicka
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V,
Enina
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Tilgale
B,
Fricbergs
J.
Combined
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AJNR
Am
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Neuroradiol
2001
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1;22(2):352-‐8.
(65)
The
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Combined
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Recanalization
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Study.
Stroke
2004
April
1;35(4):904-‐11.
(66)
Halkes
PH,
van
GJ,
Kappelle
LJ,
Koudstaal
PJ,
Algra
A.
Aspirin
plus
dipyridamole
versus
aspirin
alone
after
cerebral
ischaemia
of
arterial
origin
(ESPRIT):
randomised
controlled
trial.
Lancet
2006
May
20;367(9523):1665-‐73.
90
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3.5
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CLEAN
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protocol
Tables
Abbreviation
Description
ALDS
Academic
Medical
Center
Linear
Disability
Scale
ASPECTS
Alberta
Stroke
Program
Early
CT
score
BI
Barthel
index
CT
Computed
tomography
CTA
Computed
tomography
angiography
DMC
Data
Monitoring
Committee
DWI
Diffusion
Weighted
Imaging
EQ5D
EuroQol
5
dimensions
scale
GCS
Glasgow
Coma
Score
ICH
Intracerebral
hemorrhage
MI
Myocardial
infarction
MRA
Magnetic
Resonance
Angiography
MRI
Magnetic
Resonance
Imaging
mRS
Modified
Rankin
Scale
NIHSS
National
Institutes
of
Health
Stroke
Scale
PAD
Peripheral
arterial
disease
TICI
Thrombolysis
in
Cerebral
infarction
TICS
Telephone
Interview
for
Cognitive
Status
TIMI
Thrombolysis
in
Myocardial
Infarction
91
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17
MELT
Ia
urokinase
+/-‐
mechanical
thrombectomy
vs
114
53%
vs
(n.r.)*
29/57
vs
35/57
11%
0.8
(0.6
–
control
1.2)
19
SYNTHESIS
IA
alteplase
w/wo
MERCI
vs
I.V.
alteplase,
both
54
NR
52%
vs72%
19%
0.7
(0.5
-‐1.1)
0.9
mg/kg
ARR=absolute risk reduction; RR= relative risk; mRS= modified Rankin Scale score. Recanalization: TIMI 2+3
92
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TABLE
3
CONTROLLED
STUDIES
AND
CASE
SERIES
OF
I.V.
+
I.A.
ALTEPLASE
Intervention
(dose,
mode)
Design
NIHSS
N
SICH
Recanalization
Poor
Study
or
(%)
(N,%)
outcome
author
mRS
>2
(N,(%)
22
EMS
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
alteplase
vs
RCT
-‐
35
6%
9/11
(82%)
NR
i.a.
alteplase
alone
11%
5/10
(50%)
27
Wolfe
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
alteplase
vs
Cohort
-‐
96
12%
27/41
(66%)
22/41
i.a.
alteplase
alone
33/55
(60%)
(54%)
35/55
(64%)
25
Ernst
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
Cohort
16
5%
11/16
(69%)
6/16
(38%)
alteplase
26
Suarez
I.V.
alteplase
0.6
mg/kg
followed
by
i.a.
alteplase
/
Cohort
45
0%
18/24
(67%)
5/24
(21%)
urokinase
29
Hill
I.V.
alteplase
0.9
mg/kg
followed
by
i.a.
alteplase
Cohort
6
0%
3/6
(50%)
NR
28
Shaltoni
I.V.
alteplase
0.9
mg/kg
followed
by
i.a.
Cohort
69
6%
50/69
(73%)
45%
thrombolytics
30
Burns
I.v.
alteplase
0.9
mg/kg
followed
by
i.a.
reteplase
Cohort
33
12%
24/33
(73%)
NR
w/wo
mechanical
thrombectomy
64
Keris
IA
alteplase
25mg
followed
by
i.v.
alteplase
25
mg
RCT
45
0%
6/12
(50%)
2/12(17%)
versus
no
thrombolysis
0%
NR
22/33
(67%)
65
IMS
I
I.V.
alteplase
0.6
mg/kg
followed
by
angiography
and
Cohort
80
6.3%
35/62
(56%)
46/80
endovascular
treatment
(ia
alteplase,
heparin)
when
(58%)
indicated
24
IMS
II
I.V.
alteplase
0.6
mg/kg
followed
by
angiography
and
Cohort
81
9.9%
33/55
(60%)
44/81
endovascular
treatment
(ia
alteplase,
heparin
and
i.a.
(54%)
ultrasonography
(MicroLysUS
device)
31
Sohn
I.v.
alteplase,
followed
by
i.a.
urokinase
and/or
Cohort
14
157
12.7%
NR
NR
mechanical
thrombectomy
32
Kim
I.v.
alteplase
followed
by
urokinase
Cohort
16
18
5.6%
16/18
(89%)
9/18
(50%)
93
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38
McDougall
PENUMBRA
device
8h
18
125
102
(82%)
14
(11%)
94
(75%)
40
Zaidat
Wingspan-‐Neuroform
stents
w
8
h
18
9
8
(89%)
0
3
(33%)
or
w/o
i.a.
or
i.v.
alteplase
41
Brekenfeld
Wingspan
stents
after
failed
i.v.
8
hrs
14
12
11
(92%)
0
9
(75%)
treatment
w
or
w/o
i.v.
or
i.a.
alteplase
12
In
most
studies,
patients
treated
within
3
hrs
received
i.v.
alteplase,
and
a
small
percentage
was
treated
with
i.a.
thrombolytic.
94
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after
himself.
3
Moderate
Moderate
disability,
symptoms
that
significantly
restrict
lifestyle
disability
and
prevent
totally
independent
existence
4
Moderately
Moderately
severe
disability,
symptoms
that
clearly
prevent
severe
independent
existence
though
not
needing
constant
attention
disability
5
Severe
Severe
disability,
totally
dependent
patient
requiring
constant
disability
attention
day
and
night.
6
Dead
Death
95
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96
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NIHSS
x
x
X
Laboratory
x
x
x
Neuroimaging
x
x
X
Barthel
index
X
x
Modified
Rankin
Scale
x
EQ5D
x
97
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13
Neuro-‐imaging
parameters
will
be
assessed
by
a
central
subcommittee.
98
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Intervention
Modalities
Actual
treatment:
i.a.
thrombolysis
(urokinase,
alteplase,
other),
mechanical
treatment
(device
/type).
Timing
Time
of:
onset
(last
seen
well),
admission,
plain
CT,
CT
angiography,
(CTP),
DWI
start
of
i.v.
alteplase,
end
of
i.v.
alteplase,
start
of
endovascular
procedure
(needle
in
groin),
first
i.a.
bolus,
end
of
revascularization,
end
of
procedure.
Dosages
of
Dose
of
urokinase,
alteplase,
other
agent.
thrombolytics
Effect
of
intervention
mTICI
score
at
start
of
procedure,
mTICI
score
at
end
of
procedure
Complications
Procedure-‐related
complications
Neurological
deterioration
Follow-‐up
Clinical
assessment
at
NIH
Stroke
Scale,
NIHS
supplemental
motor
scale,
24
hours
Complications
Laboratory
parameters
SMARTIS
substudy:
5x9
cc
venous
blood
sample
Neuro-‐imaging
at
24
Plain
CT:
location,
ASPECTS
score,
hemorrhagic
transformation
hours
(NINDS/ECASS
classification),
hyperdense
artery
sign.
CT
angiography:
location,
Clot
Burden
Score/Collateral
score
CT
Perfusion:
location,
infarct
core
size,
penumbra
size,
penumbra/infarct
index
Neuro
imaging
at
5-‐7
Plain
CT:
location,
ASPECTS
score,
hemorrhagic
transformation
days
(NINDS/ECASS
classification),
hyperdense
artery
sign.
Clinical
assessment
at
NIH
stroke
scale;
Barthel
Index;
Global
assessment
of
1
wk
or
discharge
improvement
or
deterioration;
clinical
complications:
hemorrhages;
Laboratory:
GFR.
Clinical
assessment
at
Modified
Rankin
score,
Barthel
index,
EQ5D.
90
days.
Laboratory
parameters
SMARTIS
substudy:
5x9cc
venous
blood
99
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APPENDICES
COORDINATING
INVESTIGATORS
Puck
Fransen,
Dept
of
Neurology,
Erasmus
MC
Rotterdam.
Debbie
Beumer,
Dept
of
Neurology,
UMC
Maastricht.
Olvert
Berkhemer,
Dept
of
Radiology,
AMC
Amsterdam.
Lucie
van
den
berg,
Dept
of
Neurology,
AMC
Amsterdam.
PRINCIPAL
INVESTIGATORS
Diederik
Dippel,
neurologist,
Erasmus
MC
Rotterdam,
Charles
B
Majoie,
neuroradiologist,
AMC
Amsterdam,
Yvo
Roos,
neurologist,
AMC
Amsterdam,
Robert
van
Oostenbrugge,
neurologist,
UMC
Maastricht,
Aad
van
der
Lugt,
neuroradiologist,
Erasmus
MC
Rotterdam.
100
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protocol
Chair:
Professor
Martin
Brown,
National
Hospital
for
Neurology
&
Neurosurgery,
London,
UK.
Member:
Thomas
Liebig
Independent
Statistician:
Theo
Stijnen
TRIAL
STATISTICIANS
Hester
Lingsma,
methodologist,
Erasmus
MC
Rotterdam,
Ewout
Steyerberg,
methodologist,
Erasmus
MC
Rotterdam.
ADVISORY BOARD
101
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protocol
GENERAL
Randomization,
inclusion
in
the
trial
and
subsequent
endovascular
treatment
should
be
started
as
soon
as
possible
after
presentation
in
all
eligible
patients.
The
time-‐path
below
gives
an
indication
about
how
soon
the
following
steps
need
to
take
place.
TABLE
A1.
OPTIMAL
TIME-‐PATH
FOR
TREATMENT
AND
INCLUSION
IN
MR
CLEAN
OF
PATIENTS
WITH
ACUTE
ISCHEMIC
STROKE
AND
RELEVANT
ANTERIOR
CIRCULATION
ARTERIAL
INCLUSION
Procedure
Tx
with
i.v.
alteplase
No
tx
with
i.v.
alteplase
0
0
Arrival
at
ER
20
min
20
Start
neuroimaging
30
min
-‐
Start
iv-‐alteplase
60
min
30
Randomization
The
selection
process
is
shown
in
Figure
3
of
the
protocol.
Three
clinical
situations
can
be
distinguished:
1
“No
response
to
i.v.
alteplase”:
in
these
patients,
there
is
no
favorable
response
to
treatment
with
intravenous
alteplase.
Vascular
neuroimaging
(CTA,
MRA,
TCD)
may
follow
treatment
with
i.v.
alteplase,
but
the
steering
committee
recommends
that
vascular
neuroimaging
is
done
at
the
start
of
i.v.
treatment.
The
exact
definition
of
favorable
response
is
left
to
the
discretion
of
the
local
investigator,
but
the
steering
committee
suggests
the
following:
neurological
recovery
to
a
level
that
would
obviate
the
indication
for
i.v.
alteplase
would
the
patient
present
with
these
symptoms.
No
minimum
time
period
between
assessment
of
the
response
to
i.v.
alteplase
and
end
of
treatment
is
required,
but
102
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,
2014
MR
CLEAN
Trial
protocol
the
steering
committee
recommends
that
randomization
and
inclusion
into
the
trial,
andsubsequent
endovascular
treatment
should
be
started
as
soon
as
possible.
2
“Outside
therapeutic
window
for
i.v.
alteplase”:
these
patients
present
in
the
4.5
to
6
hour
window.
They
can
be
included
in
the
study,
and
randomized
for
endovascular
treatment
or
no
endovascular
treatment.
3
“
Contra-‐indications
for
i.v.
alteplase”:
these
patients
have
contraindications
for
i.v.
alteplase
that
do
not
apply
to
mechanical
thrombectomy,
for
example
a
recent
cerebral
infarction
in
a
different
vascular
area,
previous
cerebral
hemorrhage,
treatment
with
coumarines
leading
with
INR
1.7
to
3.0).
They
can
be
included
in
the
study,
and
randomized
for
endovascular
treatment
or
no
endovascular
treatment.
Intra-‐arterial
thrombolysis
is
not
recommended
for
these
patients,
but
mechanical
thrombectomy
ís.
NEUROIMAGING
Neuroimaging
studies
to
assess
vessel
patency
should
preferably
be
done
before
or
simultaneously
with
treatment
with
i.v.
alteplase,
in
order
not
to
lose
time
and
brain.
Especially,
the
delay
between
end
of
i.v.
infusion
and
start
of
endovascular
treatment
should
be
minimized
to
less
than
1
hour.
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CLEAN
Trial
protocol
TABLE
A2-‐A:
DOSING
SCHEME
FOR
INTRAVENOUS
AND
INTRA
ARTERIAL
THROMBOLYSIS
WITH
ALTEPLASE
OR
UROKINASE
Weight
Alteplase
Alteplase
Alteplase
Urokinase
Alteplase
Urokinase
(kg)
Bolus
i.v
2/3
dose
1/3
dose
equivalent
Max
total
equivalent
max
(mg)
(mg)
(mg)
1/3
Dose
dose
(mg)*
total
dose
(kU)
(U)
50
5
25
15
200
45
600
55
5
28
17
200
50
600
60
5
31
18
225
54
675
65
6
34
19
250
59
750
70
6
36
21
250
63
750
75
7
38
23
275
68
825
80
7
41
24
300
72
900
85
8
43
26
325
77
975
90
8
46
27
350
81
1,050
95
9
48
29
375
86
1,125
100
9
51
30
400
90
1,200
>100
9
51
30
400
90
1,200
MECHANICAL
THROMBECTOMY
Randomized
clinical
trials
of
devices
for
mechanical
thrombectomy
have
not
been
done.
General
criteria
for
the
use
of
devices
in
MR
CLEAN
are
publication
of
a
case
series
at
least
20
patients
treated
with
the
device,
with
an
acceptable
rate
of
complications
and
a
TIMI
2/3
recanalization
rate
of
more
than
50%.
Currently,
two
devices
for
mechanical
thrombectomy
(MERCI
and
PENUMBRA),
specifically
designed
for
treatment
of
acute
intracranial
arterial
occlusions
have
been
evaluated
in
case
series,
and
have
been
FDA
approved
for
this
purpose.
One
catheter
system,
EKossonics
SV,
designed
for
delivery
of
ultrasound-‐waves
to
the
occluding
thrombus,
has
been
evaluated
in
IMS2
and
will
be
evaluated
together
with
the
MERCI
system
in
IMS3.
These
devices
have
been
shown
to
be
capable
of
recanalization,
with
an
acceptable
rate
of
complications.39
Therefore,
Currently
the
MERCI,
Penumbra,
Solitaire
and
Ekossonics
SV
devices,
fulfill
the
requirements
as
formulated
by
the
steering
committee
(Table
A3).
Two
stent
devices
have
been
approved
for
intracranial
treatment,
but
not
for
treatment
of
patients
with
acute
ischemic
stroke,
moreover
published
experience
with
treatment
is
limited.
The
steering
committee
of
MR
CLEAN
will
be
actively
seeking
evidence
that
will
make
specific
stenting
devices
acceptable
for
use
in
the
trial.
104
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2014
MR
CLEAN
Trial
protocol
TABLE
A3.
LIST
OF
MECHANICAL
THROMBECTOMY
DEVICES
THAT
ARE
AVAILABLE
IN
THE
NETHERLANDS,
THEIR
MODE
OF
ACTION
AND
CURRENT
STATUS.
15
Device
Mode
of
Manufacturer
NL
Dealer
Approval Evaluation
14
16
action studies
Allowed
Merci
retriever
R,A
Concentric
Medical
Top
Medical
FDA
CS
Penumbra
System
A,F
Penumbra
Incm
US
Penumbra
FDA
CS
Solitaire
Stent
(ev3)
S
EV3
Ev3
CE
CS
EKossonic
SV
U
EKOS
Bothell
Wash
Angiocare
CE
CR
Pending
17
Wingspan
stent
A
Boston
Scientific
Boston
sci
FDA
CS
CATCH
device
R,A
Balt
Extrusion
Angiocare
CE
CR
Revasc
S
Micrus
Angiocare
CE
?
Moses
S
Micrus
Angiocare
CE
?
Fast
A
Micrus
Angiocare
CE
?
Vasco+35ASPI
A
Balt
Angiocare
CE
?
14
R=retraction,
A=aspiration,
S=Stenting,
F=Fragmentation,
U=
ultrasound
enhanced
lysis
15
FDA
=
Federal
Drugs
Agency,
CE
=
Conformité
Européenne,
which
means
in
concordance
with
European
legislation.
16
U=unpublished
studies
only,
CR=case
reports,
CS=case
series
17
Approved
only
for
elective
treatment
of
intracranial
stenosis.
105
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3.5
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11
,
2014
MR
CLEAN
Trial
protocol
WHEN
1)
The
pre-‐intervention
angiogram
should
be
performed
via
the
guiding
catheter
to
evaluate
the
site
of
vessel
occlusion,
extent
of
thrombus,
territories
involved,
concomittant
pathologies
and
to
assess
collateral
flow.
45
2)
After
passing
the
occlusion
site
a
microcatheter
injection
should
be
performed
to
assess
the
distal
vascular
bed.
3)
After
each
bolus
of
thrombolytic
agent
a
control
angiogram
via
a
microcatheter
injection
and/or
guiding
catheter
injection
should
be
performed
to
assess
vessel
patency.
4)
After
each
passage
of
a
mechanical
device,
a
control
angiogram
should
be
performed
via
the
guiding
catheter
to
assess
vessel
patency.
5)
At
the
end
of
the
procedure
the
angiogram
should
be
repeated
via
the
guiding
catheter
to
assess
the
final
angiographic
outcome
HOW
The
angiogram
should
include
the
internal
carotid
artery
(or
common
carotid
in
case
of
occlusion
or
severe
stenosis
of
internal
carotid)
feeding
the
target
vessel
as
demonstrated
on
CTA.
To
completely
assess
the
collateral
circulation,
injections
of
the
contralateral
internal
carotid
artery
(or
common
carotid
in
case
of
occlusion
or
severe
stenosis
of
internal)
and
the
dominant
vertebral
artery
are
preferred.
However,
they
are
not
necessary
for
inclusion
in
the
study.
AP
views
and
lateral
views
of
the
intracranial
arteries
are
obtained.
It
is
essential
that
the
angiograms
include
both
the
arterial
and
venous
phases
of
the
injection
to
evaluate
the
collateral
pathways
and
perfusion
of
the
distal
vascular
bed.
The
angiograms
should
be
performed
via
the
guiding
catheter
with
the
same
catheter
position,
contrast
injection
volume
and
rate
(6-‐8ml
with
4ml/s
for
internal
carotid,
8-‐10ml
with
4-‐6ml/s
for
common
carotid
and
6-‐8ml
with
4-‐5ml/s
for
vertebral
artery),
and
angiographic
views
before,
after
the
procedures
to
adequately
assess
the
results
of
therapy.
4. After
passing
the
occlusion
site,
after
each
bolus
of
thrombolytic
agent
and
after
each
pass
of
a
mechanical
device:
APPENDIX
5:
PROTOCOL
AMENDMENT
MR
CLEAN
TRIAL;
SUBSTANTIAL
PROTOCOL
3.1.
Amendment
1:
Add
under
Add
under
Specific
exclusion
criteria
for
intended
intra-‐arterial
thrombolysis:
106
Version
3.5
June
11
,
2014
MR
CLEAN
Trial
protocol
“
Current
treatment
with
oral
thrombin
antagonists,
such
as
argatroban
and
dabigatran
or
treatment
with
rivaroxaban,
a
selective
Factor
Xa
inhibitor.”
Rationale:
the
new
oral
factor
Xa
inhibitors
and
thrombin
antagonsists
provide
a
level
of
anticoagulation
that
is
comparable
with
cumarines
or
heparin.
It
is
very
likely
that
concomittant
treatment
with
alteplase
of
urokinase
leads
to
an
increased
risk
of
(local)
hemorrhage.
The
risk
of
treatment
with
mechanical
devices
is
likely
to
be
unchanged.
Amendment
2:
Add
under
substudies:
‘’SMARTIS:
study
of
haemostatic
markers
in
intra-‐arterial
treatment
for
acute
ischemic
stroke’’.
Rationale:
the
study
was
planned
to
be
carried
out
on
the
role
of
heamostatic
factors
as
effect
modifiers
in
endovascular
treatment
Amendment
3:
Replace
vacancy
under
after
AMC
Amsterdam
under
appendix
1,
coordinating
investigators
by:
Olvert
Berkhemer
Amendment
4:
Replace
vacancy
under
after
UMC
Maastricht
under
appendix
1,
coordinating
investigators
by:
Debbie
Beumer
Amendment
5:
Replace
Trude
Leertouwer
by
Sjoerd
Jenniskens,
neuroradiologist,
UMC
Nijmegen
under
appendix
2,Imaging
assessment
committee
Amendment
6:
Replace
vacancy
under
appendix
2,
outcome
assessment
committee
by
Ewoud
van
Dijk,
neurologist
UMC
St.
Radboud,
Nijmegen
,
Jelis
Boiten,
neurologist
MC
Haaglanden,
Den
Haag.
Amendment
7:
Replace
vacancy
under
appendix
2,
adverse
event
committee
by
Zwenneke
Flach,
Radiologist,
Isala
Kliniek
Zwolle,
Marieke
Wermer,
Neurologist,
LUMC
Leiden
107
Version
3.5
June
11
,
2014
MR
CLEAN
Trial
protocol
for
intra
arterial
treatment
in
that
particular
center
the
so
called
‘randomization
center’
will
continue
to
randomize
the
patients.
If
the
patient
is
randomized
in
the
intra
arterial
treatment
arm,
the
patient
will
be
transferred
to
the
MEC
approved
MR
CLEAN
center.
If
the
patient
is
randomized
in
the
control
arm
the
patient
will
be
monitored
in
this
randomization
center.
Amendment
4:
Add
under
substudies:
“DIANE:
Value
of
Diffusion-‐Weighted
MRI
for
Selection
of
Patients
for
IA
Treatment
for
Acute
Ischemic
Stroke
in
the
NEtherlands.”
For
further
explanation
we
refer
to
the
separate
protocol.
Amendment
5:
Add
under
Tables,
“Table
1
Abbreviations”:
DWI
“Diffusion
Weighted
Imaging”
Amendment
6:
Added
M2
branche
2
and
adjusted
M2
branche
1
under
“Table
5c
CLOT
BURDEN
SCORE’.
Sum
score
is
now
10.
Amendment
7:
Add
under
Tables,
Table
6b.
List
of
study
data,
Baseline:
“If
possible
DWI:
location
and
infarct
core
size.
And
under
intervention:
DWI
Amendment
8:
Deleted
under
Tables,
Table
6b:
List
of
study
data,
Follow-‐up:
Deleted
NIHSS
stroke
scale
at
90
days.
Amendment
9:
Appendix
1,
coordinating
investigators:
Formatting
and
hierarchy
of
names
was
changed.
Added
Dept
of
Radiology
to
Olvert
Berkhemer
Amendment
10:
Added
three
local
principal
investigators
changed
two
others,
to
the
table
in
APPENDIX
1
LIST
OF
COLLABORATIONG
INVESTIGATORS.
Table
“Local
principal
investigators”.
Amendment
11:
Added
2
members
to
the
imagine
committee
in
Appendix
2
“Imaging
Assessment
Committee”
APPENDIX
7:
PROTCOL
AMENDMENT
MR
CLEAN
TRIAL;
SUBSTANTIAL
PROTOCOL
3.3
Substantial
changes:
Amendment
1:
Added
under
“List
of
authors
under
the
main
title”:
junior
researcher
4
:
Lucie
A.
van
den
Berg
was
added,
Rationale
of
change:
this
junior
researcher
is
added
to
investigate
the
economic
evaluation
and
long-‐term
follow
up
of
the
MR
CLEAN
trial.
Amendment
2:
On
page
18
under
paragraph
6.
Methods,
under
Functional
Outcome,
removed
from
the
original
text:
Score
on
the
Academic
Medical
Centre
Linear
Disability
Scale
at
90
Days
and
Score
of
Telephone
Interview
on
Cognitive
Status
(TICS)
at
90
days.
Rationale
of
change:
two
measurements
were
removed
due
to
practical
problems
of
implementing
the
Academic
Medical
Centre
Linear
Disability
Scale
and
time
management
problems
during
the
telephone
interview
at
three
months.
Amendment
3:
On
page
18
under
paragraph
6.
Methods,
under
Data
for
cost-‐effectiveness
analysis,
added
to
the
original
text:
Therefore
a
separate
substudy
on
cost-‐effectiveness
will
be
carried
out
(see
10.2
substudies
and
the
separate
substudy
protocol
for
more
detailed
information).
Rationale
of
change:
sentence
was
added
to
announce
a
substudy
on
economic
evaluation.
108
Version
3.5
June
11
,
2014
MR
CLEAN
Trial
protocol
Amendment
4:
On
page
20
under
paragraph
6.4
Study
procedures,
removed
from
the
original
text:
Academic
Medical
Centre
Linear
Disability
Scale
and
TICS.
Rationale
of
change:
see
Amendment
2.
Amendment
5:
On
page
23
under
paragraph
10
Administrative
aspects
and
publication,
under
10.2
substudies,
added
to
the
original
text:
Furthermore
we
will
carry
out
a
third
substudy
on
long
term
follow-‐up
and
cost-‐effectiveness
of
endovascular
treatment
(Roos)
.
For
this
study
the
follow-‐up
will
be
extended
to
two
years.
We
refer
to
a
separate
substudy
protocol
for
a
detailed
description
(
‘CLOT-‐MR
CLEAN:
Cost-‐effectiveness
analyses
and
LOng
Term
follow-‐up
in
patients
randomised
in
a
multicenter
randomized
clinical
trial
of
endovascular
treatment
for
acute
ischemic
stroke
in
The
Netherlands’).
Rationale
of
change:
The
MR
CLEAN
trial
is
an
ideal
setting
for
measuring
the
societal
costs
related
to
endovascular
treatment
after
stroke
,
thereby
enabling
a
full
economic
evaluation
of
cerebral
endovascular
treatment
against
standard
care.
The
time
horizon
will
be
two
years.
Within
this
time
horizon
the
MR
CLEAN
trial
itself
will
answer
the
question
whether
higher
recanalization
rates
improve
functional
outcome
and
quality
of
life
(see
separate
substudy
protocol
CLOT-‐MR
CLEAN).
Amendment
6:
On
page
36,
under
TABLE
6A.
Schedule
of
study
activities,
removed
from
table:
Academic
Medical
Centre
Linear
Disability
Scale
and
TICS.
Rationale
of
change:
see
Amendment
2.
Amendment
7:
On
page
38,
under
TABLE
6B.
List
of
study
data,
removed
from
table:
Academic
Medical
Centre
Linear
Disability
Scale
and
TICS.
Rationale
of
change:
see
Amendment
2.
Non
substantial
administrative
changes:
Non
substantial
amendment
1:
On
page
23
under
paragraph
10
Administrative
aspects
and
publication,
under
10.2
substudies,
the
original
text
:
replaced
Another
for
A
second
Non
substantial
amendment
2:
On
page
23
under
paragraph
10
Administrative
aspects
and
publication,
under
10.2
substudies,
The
original
text
A
substudy
on
costs
and
cost-‐
effectiveness
of
endovascular
treatment
(Roos),
and
on
clinical
and
radiological
predictors
of
recanalization
(Majoie)
and
functional
outcome
after
treatment
(Dippel).
Interobserver
and
validation
studies
of
rapid
reperfusion
scores
will
be
carried
out,
was
replaced
by:
A
substudy
on
clinical
and
radiological
predictors
of
recanalization
(Majoie)
and
functional
outcome
after
treatment
(Dippel)
as
well
as
interobserver
and
validation
studies
of
rapid
reperfusion
scores
will
be
carried
out.
Non
substantial
amendment
3:
On
page
39,
under
Appendix
1.
List
of
collaborating
investigators,
under
Coordinating
investigators,
one
new
junior
researcher
was
added:
Lucie
van
den
berg,
Dept
of
Neurology,
AMC
Amsterdam,
see
.
Non
substantial
amendment
4
:
On
page
39,
under
Appendix
1.
List
of
collaborating
investigators,
under
local
principal
investigators
J.
de
Vries
was
replaced
by
J.
van
Dijk
as
interventionist
at
the
HAGA
Ziekenhuis
Den
Haag.
109
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CLEAN
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protocol
Non
substantial
amendment
5:
On
page
40,
under
Appendix
2.
Study
committees,
under
Executive
and
Writing
committee,
one
new
junior
researcher
was
added
:
Lucie
van
den
Berg,
research
coordinator
on
the
economic
evaluation
and
long-‐term
follow-‐up,
AMC
Amsterdam
and
one
methodologist:
Hester
Lingsma,
methodologist,
Erasmus
MC
Rotterdam,was
added.
APPENDIX
8:
PROTOCOL
AMENDMENT
MR
CLEAN
TRIAL;
SUBSTANTIAL
PROTOCOL
3.4
Substantial
changes:
Amendment
1:
Added
two
new
centers.
One
center,
Medisch
Spectrum
Twente,
will
be
a
MR
CLEAN
intervention
center
and
will
start
patient
treatment
after
complying
with
the
protocol
guidelines.
The
other
center,
Sint
Lucas
Andreas,
will
only
randomize
patients;
intra-‐arterial
treatment
will
be
provided
by
the
Academic
Medical
Center
Amsterdam.
(Adjustments
can
be
found
on
page
2,
3
and
39)
Amendment
2:
Moved
the
exclusion
criterion:
“Cerebral
infarction
in
the
distribution
of
the
relevant
occluded
artery
in
the
previous
6
weeks”
from
“specific
exclusion
criteria
for
intended
intra-‐aterial
thrombolysis”
to
“general
exclusion
criteria”.
Rationale;
this
criterion
was
accidently
placed
under
specific
instead
of
general.
Amendment
3:
Changed
on
page
39,
the
status
of
the
Atrium
MC
to
active
MR
CLEAN
treatment
center.
The
Atrium
MC
may
start
treatment
after
complying
with
the
protocol
guidelines.
Treatment
of
patients
is
done
in
close
collaboration
with
Maastricht
University
Medical
Center.
Non
substantial
changes
administrative
changes:
Non
substantial
amendment
1:
Correction
of
table
5C
“Clot
Burden
score
for
CTA
and
MRA’
on
page
35.
Added
an
extra
M2
branch
in
the
table,
this
was
a
typo
in
the
original
table.
Non
substantial
amendment
2:
Added
in
Appendix
2
“Study
Committees”.
Added
O.A.
Berkhemer
to
the
Imaging
Assessment
committee.
110
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CLEAN
Trial
protocol
Non
substantial
amendment
5:
Added
APPENDIX
10:
(predefined)
Statiscal
Analysis
Plan
(SAP).
Rationale:
SAP
was
added
as
an
appendix
to
the
manuscript
we
submitted
to
Trials,
which
now
has
been
provisionally
accepted.
The
SAP
defines
our
prespecified
subgroup
analyses
before
closure
of
the
database
and
deblinding
(page
50).
111
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2014
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CLEAN
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protocol
INTRODUCTION
The
purpose
of
the
Multi
Center
Randomized
Clinical
trial
of
Endovascular
treatment
in
The
Netherlands
(MR
CLEAN)
is
to
assess
the
safety
and
effect
on
functional
outcome
of
intra-‐
arterial
treatment
in
patients
with
acute
ischemic
stroke
caused
by
intracranial
arterial,
anterior
circulation
occlusion.
Here
we
will
summarize
the
statistical
analysis
of
the
data.
We
will
describe
how
missing
data
will
be
handled
and
subgroup
analyses
will
be
performed.
Moreover,
we
will
describe
the
time
path
of
the
analyses
and
the
process
of
deblinding,
as
well
as
reporting
to
the
Data
Monitoring
and
Safety
Committee
(DMSC).
Although
we
list
an
extensive
number
of
analyses,
we
do
not
imply
that
all
these
will
be
described
in
the
main
paper,
because
of
space
restrictions.
RESEARCH QUESTIONS
112
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3.5
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2014
MR
CLEAN
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protocol
TRIAL
DESIGN
This
is
a
multicenter
clinical
trial
with
randomized
treatment
allocation,
open
label
treatment
and
blinded
endpoint
evaluation
(PROBE
design).
The
intervention
contrast
is
intra-‐arterial
treatment
(alteplase
or
urokinase,
and/or
mechanical
treatment)
versus
no
intra-‐arterial
treatment.
The
treatment
is
provided
in
addition
to
best
medical
management,
which
may
include
intravenous
alteplase.
Randomization
was
stratified
for
center,
dichotomized
score
on
the
National
Institutes
of
Health
Stroke
Scale
(NIHSS),[1]
treatment
with
iv
alteplase
and
intended
mechanical
treatment.
• A
clinical
diagnosis
of
acute
stroke,
with
a
deficit
on
the
NIH
stroke
scale
of
2
points
or
more.
• CT
or
MRI
scan
ruling
out
intracranial
hemorrhage.
• Intracranial
arterial
occlusion
of
the
distal
intracranial
carotid
artery
or
middle
(M1/M2)
or
anterior
(A1/A2)
cerebral
artery,
demonstrated
with
CTA,
MRA,
DSA.
• The
possibility
to
start
treatment
within
6
hours
from
onset.
• Informed
consent
given.
• Age
18
or
over.
113
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Laboratory
evidence
of
coagulation
abnormalities,
i.e.
platelet
count
<40
x
109/L,
•
APTT>50
sec
or
INR
>3.0.
Specific
exclusion
criteria
for
intended
intra-‐arterial
thrombolysis
are:
• Vessel
recanalization
at
24
hours
after
treatment,
assessed
by
CTA
or
MRA.
The
criteria
for
recanalization
on
CTA
or
MRA
are
based
on
the
Arterial
Occlusive
Lesion
(AOL)
scale,[2]
and
the
Clot
Burden
Score.[3]
• Infarct
size
assessed
by
CT
on
day
5-‐7,
using
standard
methods,
including
manual
tracing
of
the
infarct
perimeter
and
semiautomated
pixel
thresholding.[4,
5]
• Score
on
the
National
Institutes
of
Health
Stroke
Scale
(NIHSS)
at
24
hours.
• Score
on
the
NIHSS
at
1
week
or
at
discharge.
• Score
on
the
EQ5D
at
90
days,[6]
• Barthel
index
at
90
days.[7]
The
primary
safety
parameter
was
neurologic
deterioration
within
24
hours
from
inclusion
in
the
study.
Neurological
deterioration
was
defined
as
any
decline
in
NIHSS
of
more
than
4
points.
In
these
patients,
urgent
brain
CT
is
mandatory.
This
serious
adverse
event
was
further
classified
as
due
to
intracranial
hemorrhage,
ischemia
or
other
(undetermined)
cause.
BLINDING
114
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CLEAN
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protocol
It
was
not
possible
to
view
the
treatment
allocation
before
the
patient
was
registered
in
the
study
database,
nor
was
it
possible
to
remove
the
patient
from
the
study
base
after
treatment
assignment
has
become
known.
Both
patient
and
treating
physician
were
aware
of
the
treatment
assignment.
Information
on
outcome
at
three
months
was
assessed
through
standardized
forms
and
procedures
by
a
dedicated
research
nurse.
Assessment
of
outcome
on
the
modified
Rankin
scale
was
based
on
this
information,
by
assessors
who
were
blind
to
the
treatment
allocation.
Results
of
neuroimaging
were
also
assessed
in
a
blinded
manner.
Information
on
treatment
allocation
and
90-‐day
outcome
was
kept
separate
from
the
main
study
database.
The
steering
committee
members
were
kept
unaware
of
the
results
of
interim
analyses
of
efficacy
and
safety.
The
trial
statistician
combined
data
on
treatment
allocation
with
the
clinical
data
in
order
to
report
to
the
data
monitoring
and
safety
committee
(DMSC)
in
a
closed
session.
• age,
• stroke
severity
(NIHSS)
at
baseline
• time
to
randomization
• previous
stroke,
• atrial
fibrillation,
• diabetes
mellitus
and
• carotid
top
occlusion
versus
no
carotid
top
occlusion
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• Extracranial
>50%
carotid
stenosis
or
occlusion
versus
no
>50%
carotid
stenosis
or
occlusion
• ASPECTS
0-‐4
/
5-‐7
/
8-‐10
• Thrombus
length
>7mm
versus
7
mm
or
less.
Secondary
effect
parameters
will
be
the
improvement
according
to
the
classical
dichotomizations
of
the
modified
Rankin
scale,
neurological
deficit
at
24
hours
and
1
week
measured
with
the
NIHSS,
quality
of
life
at
90
days
measured
with
EQ5D
and
vessel
patency
at
24
hours
as
well
as
infarct
size
at
5-‐7
days
on
CT
or
MRI.
Effect
parameter
in
these
first
four
analyses
will
be
the
odds
ratio,
estimated
with
multiple
logistic
regression.
The
effect
parameter
on
the
fourth
to
sixth
outcome
(EQ5D
and
NIHSS)
will
be
a
regression
parameter
beta,
estimated
with
multiple
linear
regression
models.
Outcome
data
may
have
to
be
log-‐transformed.
The
clot
burden
score
will
be
dichotomized
into
10
or
less
than
10
and
the
effect
parameter
will
be
the
odds
ratio,
estimated
with
multiple
logistic
regression.
The
effect
on
infarct
size
will
be
estimated
with
a
multiple
linear
regression
model.
In
all
analyses,
statistical
uncertainty
will
be
expressed
by
means
of
95%
confidence
intervals.
Although
the
size
of
this
study
does
not
allow
for
precise
estimates
of
treatment
effect
in
subgroups,
we
assess
heterogeneity
of
effects,
and
analyze
consistency
of
effects
on
secondary
outcomes.
TIME
PATH
OF
THE
ANALYSES
AND
LOCKING
OF
THE
DATABASE.
116
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protocol
To
maximize
time
for
analysis
and
interpretation
of
the
results
and
allow
presentation
of
the
final
results
at
the
World
Stroke
Conference
by
the
end
of
October
2014,
a
soft-‐lock
and
preliminary
analysis
will
be
performed
once
the
last
patients
have
had
their
final
outcome
recorded
and
the
data
has
been
reviewed
by
the
DMSC
by
mid
July
2014.
Following
final
data
cleaning
on
the
last
patients
to
be
recruited,
a
hard-‐lock
will
be
performed
by
mid
September.
The
results
of
this
analysis
will
be
considered
by
the
Trial
Steering
Committee
by
the
end
of
September,
2014.
The
preliminary
interpretation
will
be
performed
after
soft-‐lock
by
DD,
CM
and
HL;
they
will
not
be
involved
in
resolving
any
final
queries
to
maintain
the
integrity
and
blinding
of
the
final
database.
The
approach
of
soft-‐lock
then
hard-‐lock
is
a
standard
approach
in
large
trials
and
allows
more
time
to
be
spent
on
considering
the
results
of
a
trial,
their
interpretation
and
presentation
for
publication.
REFERENCES
1.
Brott
T,
Adams
HP,
Jr.,
Olinger
CP,
Marler
JR,
Barsan
WG,
Biller
J,
Spilker
J,
Holleran
R,
Eberle
R,
Hertzberg
V
et
al:
Measurements
of
acute
cerebral
infarction:
a
clinical
examination
scale.
Stroke
1989,
20(7):864-‐870.
2.
Higashida
RT,
Furlan
AJ:
Trial
Design
and
Reporting
Standards
for
Intra-‐Arterial
Cerebral
Thrombolysis
for
Acute
Ischemic
Stroke.
Stroke
2003,
34(8):e109-‐e137.
3.
Puetz
V,
Dzialowski
I,
Hill
MD,
Subramaniam
S,
Sylaja
PN,
Krol
A,
O'Reilly
C,
Hudon
ME,
Hu
WY,
Coutts
SB
et
al:
Intracranial
thrombus
extent
predicts
clinical
outcome,
final
infarct
size
and
hemorrhagic
transformation
in
ischemic
stroke:
the
clot
burden
score.
International
journal
of
stroke
:
official
journal
of
the
International
Stroke
Society
2008,
3(4):230-‐236.
4.
van
der
Worp
HB,
Claus
SP,
Bar
PR,
Ramos
LM,
Algra
A,
van
GJ,
Kappelle
LJ:
Reproducibility
of
measurements
of
cerebral
infarct
volume
on
CT
scans.
Stroke
2001,
32(2):424-‐430.
5.
Gavin
CM,
Smith
CJ,
Emsley
HC,
Hughes
DG,
Turnbull
IW,
Vail
A,
Tyrrell
PJ:
Reliability
of
a
semi-‐
automated
technique
of
cerebral
infarct
volume
measurement
with
CT.
CerebrovascDis
2004,
18(3):220-‐226.
6.
EuroQol
Group
T:
EuroQol-‐a
new
facility
for
the
measurement
of
health-‐related
quality
of
life.
Health
Policy
1990,
16(3):199-‐208.
7. Mahoney FI, Barthel DW: Functional Evaluation: The Barthel Index. Md State Med J 1965, 14:61-‐65.
8.
McHugh
GS,
Butcher
I,
Steyerberg
EW,
Marmarou
A,
Lu
J,
Lingsma
HF,
Weir
J,
Maas
AI,
Murray
GD:
A
simulation
study
evaluating
approaches
to
the
analysis
of
ordinal
outcome
data
in
randomized
controlled
trials
in
traumatic
brain
injury:
results
from
the
IMPACT
Project.
Clin
Trials
2010,
7(1):44-‐
57.
9.
Hernandez
AV,
Steyerberg
EW,
Butcher
I,
Mushkudiani
N,
Taylor
GS,
Murray
GD,
Marmarou
A,
Choi
SC,
Lu
J,
Habbema
JD
et
al:
Adjustment
for
strong
predictors
of
outcome
in
traumatic
brain
injury
trials:
25%
reduction
in
sample
size
requirements
in
the
IMPACT
study.
J
Neurotrauma
2006,
23(9):1295-‐
1303.
117
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3.5
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MR
CLEAN
Trial
protocol
FIGURES
118
Version
3.5
June
11
,
2014
MR
CLEAN
Trial
protocol
FIGURE
2
Assumed
distribution
of
the
primary
outcome,
according
to
the
modified
Rankin
scale
in
group
receiving
no
intra-‐arterial
treatment
(mRS-‐C)
(control)
and
the
group
receiving
intra-‐
arterial
treatment
(mRS-‐I).
THe
cumulative
proportion
of
patients
in
mRS
0-‐3
has
increased
with
10%.
proportion
mRS_C
mRS_I
mRS score
119
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CLEAN
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protocol
FIGURE 3. RANDOMIZATION AND INCLUSION OF PATIENTS IN THE TRIAL
120
Version
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11
,
2014
MR
CLEAN
Trial
protocol
Recommendations
on
angiographic
revascularization
grading
standards
for
acute
ischemic
stroke:
a
consensus
statement.
Stroke;
a
journal
of
cerebral
circulation.
2013;44(9):2650-‐63.
121
INTRODUCTION
The
purpose
of
the
Multi
Center
Randomized
Clinical
trial
of
Endovascular
treatment
in
The
Netherlands
(MR
CLEAN)
is
to
assess
the
safety
and
effect
on
functional
outcome
of
intra-‐arterial
treatment
in
patients
with
acute
ischemic
stroke
caused
by
intracranial
arterial,
anterior
circulation
occlusion.
Here
we
will
summarize
the
statistical
analysis
of
the
data.
We
will
describe
how
missing
data
will
be
handled
and
subgroup
analyses
will
be
performed.
Moreover,
we
will
describe
the
time
path
of
the
analyses
and
the
process
of
deblinding,
as
well
as
reporting
to
the
Data
Monitoring
and
Safety
Committee
(DMSC).
Although
we
list
an
extensive
number
of
analyses,
we
do
not
imply
that
all
these
will
be
described
in
the
main
paper,
because
of
space
restrictions.
RESEARCH QUESTIONS
122
with
regard
to
obtaining
recanalization,
and
to
evaluate
predictors
of
recanalization,
including
imaging
aspects
and
hemostatic
parameters.
Moreover,
we
want
to
assess
the
safety
and
efficacy
of
different
types
of
endovascular
treatment
(i.e.
mechanical
treatment,
intra-‐arterial
thrombolysis)
different
combinations
of
treatment
(i.e.
with
intravenous
alteplase)
and
different
timings
of
treatment.
TRIAL
DESIGN
This
is
a
multicenter
clinical
trial
with
randomized
treatment
allocation,
open
label
treatment
and
blinded
endpoint
evaluation
(PROBE
design).
The
intervention
contrast
is
intra-‐arterial
treatment
(alteplase
or
urokinase,
and/or
mechanical
treatment)
versus
no
intra-‐arterial
treatment.
The
treatment
is
provided
in
addition
to
best
medical
management,
which
may
include
intravenous
alteplase.
Randomization
was
stratified
for
center,
dichotomized
score
on
the
National
Institutes
of
Health
Stroke
Scale
(NIHSS),[1]
treatment
with
iv
alteplase
and
intended
mechanical
treatment.
• A
clinical
diagnosis
of
acute
stroke,
with
a
deficit
on
the
NIH
stroke
scale
of
2
points
or
more.
• CT
or
MRI
scan
ruling
out
intracranial
hemorrhage.
• Intracranial
arterial
occlusion
of
the
distal
intracranial
carotid
artery
or
middle
(M1/M2)
or
anterior
(A1/A2)
cerebral
artery,
demonstrated
with
CTA,
MRA,
DSA.
• The
possibility
to
start
treatment
within
6
hours
from
onset.
• Informed
consent
given.
• Age
18
or
over.
123
• Vessel
recanalization
at
24
hours
after
treatment,
assessed
by
CTA
or
MRA.
The
criteria
for
recanalization
on
CTA
or
MRA
are
based
on
the
Arterial
Occlusive
Lesion
(AOL)
scale,[2]
and
the
Clot
Burden
Score.[3]
• Infarct
size
assessed
by
CT
on
day
5-‐7,
using
standard
methods,
including
manual
tracing
of
the
infarct
perimeter
and
semiautomated
pixel
thresholding.[4,
5]
• Score
on
the
National
Institutes
of
Health
Stroke
Scale
(NIHSS)
at
24
hours.
• Score
on
the
NIHSS
at
1
week
or
at
discharge.
• Score
on
the
EQ5D
at
90
days,[6]
• Barthel
index
at
90
days.[7]
The
primary
safety
parameter
was
neurologic
deterioration
within
24
hours
from
inclusion
in
the
study.
Neurological
deterioration
was
defined
as
any
decline
in
NIHSS
of
more
than
4
points.
In
these
patients,
urgent
brain
CT
is
mandatory.
This
serious
adverse
event
was
further
classified
as
due
to
intracranial
hemorrhage,
ischemia
or
other
(undetermined)
cause.
BLINDING
It
was
not
possible
to
view
the
treatment
allocation
before
the
patient
was
registered
in
the
study
database,
nor
was
it
possible
to
remove
the
patient
from
the
study
base
after
treatment
assignment
has
become
known.
Both
patient
and
treating
physician
were
aware
of
the
treatment
assignment.
Information
on
outcome
at
three
months
was
assessed
through
standardized
forms
and
procedures
by
a
dedicated
research
nurse.
Assessment
of
outcome
on
the
modified
Rankin
scale
124
was
based
on
this
information,
by
assessors
who
were
blind
to
the
treatment
allocation.
Results
of
neuroimaging
were
also
assessed
in
a
blinded
manner.
Information
on
treatment
allocation
and
90-‐day
outcome
was
kept
separate
from
the
main
study
database.
The
steering
committee
members
were
kept
unaware
of
the
results
of
interim
analyses
of
efficacy
and
safety.
The
trial
statistician
combined
data
on
treatment
allocation
with
the
clinical
data
in
order
to
report
to
the
data
monitoring
and
safety
committee
(DMSC)
in
a
closed
session.
• age,
• stroke
severity
(NIHSS)
at
baseline
• time
to
randomization
• previous
stroke,
• atrial
fibrillation,
• diabetes
mellitus
and
• carotid
top
occlusion
versus
no
carotid
top
occlusion
125
Secondary
effect
parameters
will
be
the
improvement
according
to
the
classical
dichotomizations
of
the
modified
Rankin
scale,
neurological
deficit
at
24
hours
and
1
week
measured
with
the
NIHSS,
quality
of
life
at
90
days
measured
with
EQ5D
and
vessel
patency
at
24
hours
as
well
as
infarct
size
at
5-‐7
days
on
CT
or
MRI.
Effect
parameter
in
these
first
four
analyses
will
be
the
odds
ratio,
estimated
with
multiple
logistic
regression.
The
effect
parameter
on
the
fourth
to
sixth
outcome
(EQ5D
and
NIHSS)
will
be
a
regression
parameter
beta,
estimated
with
multiple
linear
regression
models.
Outcome
data
may
have
to
be
log-‐transformed.
The
clot
burden
score
will
be
dichotomized
into
10
or
less
than
10
and
the
effect
parameter
will
be
the
odds
ratio,
estimated
with
multiple
logistic
regression.
The
effect
on
infarct
size
will
be
estimated
with
a
multiple
linear
regression
model.
In
all
analyses,
statistical
uncertainty
will
be
expressed
by
means
of
95%
confidence
intervals.
Although
the
size
of
this
study
does
not
allow
for
precise
estimates
of
treatment
effect
in
subgroups,
we
assess
heterogeneity
of
effects,
and
analyze
consistency
of
effects
on
secondary
outcomes.
TIME
PATH
OF
THE
ANALYSES
AND
LOCKING
OF
THE
DATABASE.
To
maximize
time
for
analysis
and
interpretation
of
the
results
and
allow
presentation
of
the
final
results
at
the
World
Stroke
Conference
by
the
end
of
October
2014,
a
soft-‐lock
and
preliminary
analysis
will
be
performed
once
the
last
patients
have
had
their
final
outcome
recorded
and
the
data
has
been
reviewed
by
the
DMSC
by
end
of
July
2014.
Following
final
data
cleaning
on
the
last
patients
to
be
recruited,
a
hard-‐lock
will
be
performed
by
mid
September.
The
results
of
this
126
analysis
will
be
considered
by
the
Trial
Steering
Committee
by
the
end
of
September,
2014.
The
preliminary
interpretation
will
be
performed
after
soft-‐lock
by
DD,
CM
and
HL;
they
will
not
be
involved
in
resolving
any
final
queries
to
maintain
the
integrity
and
blinding
of
the
final
database.
The
approach
of
soft-‐lock
then
hard-‐lock
is
a
standard
approach
in
large
trials
and
allows
more
time
to
be
spent
on
considering
the
results
of
a
trial,
their
interpretation
and
presentation
for
publication.
REFERENCES
1.
Brott
T,
Adams
HP,
Jr.,
Olinger
CP,
Marler
JR,
Barsan
WG,
Biller
J,
Spilker
J,
Holleran
R,
Eberle
R,
Hertzberg
V
et
al:
Measurements
of
acute
cerebral
infarction:
a
clinical
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scale.
Stroke
1989,
20(7):864-‐870.
2.
Higashida
RT,
Furlan
AJ:
Trial
Design
and
Reporting
Standards
for
Intra-‐Arterial
Cerebral
Thrombolysis
for
Acute
Ischemic
Stroke.
Stroke
2003,
34(8):e109-‐e137.
3.
Puetz
V,
Dzialowski
I,
Hill
MD,
Subramaniam
S,
Sylaja
PN,
Krol
A,
O'Reilly
C,
Hudon
ME,
Hu
WY,
Coutts
SB
et
al:
Intracranial
thrombus
extent
predicts
clinical
outcome,
final
infarct
size
and
hemorrhagic
transformation
in
ischemic
stroke:
the
clot
burden
score.
International
journal
of
stroke
:
official
journal
of
the
International
Stroke
Society
2008,
3(4):230-‐236.
4.
van
der
Worp
HB,
Claus
SP,
Bar
PR,
Ramos
LM,
Algra
A,
van
GJ,
Kappelle
LJ:
Reproducibility
of
measurements
of
cerebral
infarct
volume
on
CT
scans.
Stroke
2001,
32(2):424-‐430.
5.
Gavin
CM,
Smith
CJ,
Emsley
HC,
Hughes
DG,
Turnbull
IW,
Vail
A,
Tyrrell
PJ:
Reliability
of
a
semi-‐automated
technique
of
cerebral
infarct
volume
measurement
with
CT.
CerebrovascDis
2004,
18(3):220-‐226.
6.
EuroQol
Group
T:
EuroQol-‐a
new
facility
for
the
measurement
of
health-‐related
quality
of
life.
Health
Policy
1990,
16(3):199-‐208.
7.
Mahoney
FI,
Barthel
DW:
Functional
Evaluation:
The
Barthel
Index.
Md
State
Med
J
1965,
14:61-‐65.
8.
McHugh
GS,
Butcher
I,
Steyerberg
EW,
Marmarou
A,
Lu
J,
Lingsma
HF,
Weir
J,
Maas
AI,
Murray
GD:
A
simulation
study
evaluating
approaches
to
the
analysis
of
ordinal
outcome
data
in
randomized
controlled
trials
in
traumatic
brain
injury:
results
from
the
IMPACT
Project.
Clin
Trials
2010,
7(1):44-‐57.
9.
Hernandez
AV,
Steyerberg
EW,
Butcher
I,
Mushkudiani
N,
Taylor
GS,
Murray
GD,
Marmarou
A,
Choi
SC,
Lu
J,
Habbema
JD
et
al:
Adjustment
for
strong
predictors
of
outcome
in
traumatic
brain
injury
trials:
25%
reduction
in
sample
size
requirements
in
the
IMPACT
study.
J
Neurotrauma
2006,
23(9):1295-‐1303.
127
Summary
of
changes
between
original
and
last
version
(3.1)
of
the
Statistical
Analysis
Plan:
The
original
text
of
the
predefined
SAP
is
displayed
on
the
left
side
of
the
table.
On
the
right,
the
text
as
can
be
found
in
the
last
version
of
the
SAP.
Changes
between
the
versions
are
in
bold
typography.
Original
Changed
Vessel
recanalization
at
24
hours
after
treatment,
Vessel
recanalization
at
24
hours
after
treatment,
assessed
by
CTA
or
MRA.
The
criteria
for
assessed
by
CTA
or
MRA.
The
criteria
for
recanalization
on
CTA
or
MRA
are
based
on
a
recanalization
on
CTA
or
MRA
are
based
on
the
simplified
TICI
score,[2]
and
the
clot
burden
Arterial
Occlusive
Lesion
(AOL)
scale,[2]
and
the
score.[3]
Clot
Burden
Score.[3]
To
maximize
time
for
analysis
and
interpretation
To
maximize
time
for
analysis
and
interpretation
of
the
results
and
allow
presentation
of
the
final
of
the
results
and
allow
presentation
of
the
final
results
at
the
World
Stroke
Conference
by
the
results
at
the
World
Stroke
Conference
by
the
end
of
October
2014,
a
soft-‐lock
and
preliminary
end
of
October
2014,
a
soft-‐lock
and
preliminary
analysis
will
be
performed
once
the
last
patients
analysis
will
be
performed
once
the
last
patients
have
had
their
final
outcome
recorded
and
the
have
had
their
final
outcome
recorded
and
the
data
has
been
reviewed
by
the
DMSC
by
mid
July
data
has
been
reviewed
by
the
DMSC
by
end
of
2014.
July
2014.
128