Plain English Summary
Background and study aims
Ischaemic strokes occur when a blood clot blocks the flow of blood to the brain. Intra-arterial thrombolysis and mechanical thrombectomy is a new and promising treatment for patients with acute ischemic stroke. This treatment involves going into the brain arteries with a very small tube (catheter) to deliver treatment at the site of the blocked blood vessel that caused the stroke, reopening the blocked vessels and removing the clot. This study will investigate the effectiveness and safety of this treatment.
Who can participate?
Patients with acute ischemic stroke who admitted to the ER of one of the participating medical centers within 6 hours from onset of symptoms.
What does the study involve?
Participants are randomly allocated to receive either standard treatment for acute ischemic stroke or intra-arterial treatment as described above. Participants then undergo additional MRI or CT scans to check whether the blocked vessel has been reopened. After 1 week, a CT scan is carried out to assess the extent of the stroke. Blood is drawn at this time to look for blood clotting abnormalities. After 3 months, participants are approached by telephone to check on their general condition.
What are the possible benefits and risks of participating?
Those who participate in the study will benefit from high level stroke assessment by experienced stroke neurologists. As the effectiveness of the treatment is not yet proven, the opportunity to receive this treatment cannot be called a benefit. The treatment is probably associated with an increased risk of bleeding inside the skull and at the site of the cather insertion in the groin. Early studies so far suggest that the risks of the treatment are in balance with the expected benefit.
Where is the study run from?
In 14 large hospitals in the Netherlands, listed on the trial website: http://www.mrclean-trial.org/centers.htm
When is the study starting and how long is it expected to run for?
December 2010 to January 2015
Who is funding the study?
The project is funded by the Dutch Heart Foundation, and by several companies, all of whom are listed on the trial website: http://www.mrclean-trial.org/sponsors.htm
Who is the main contact?
Prof. Diederik Dippel and Prof. Charles Majoie
mrclean@erasmusmc.nl
Trial website
Contact information
Type
Scientific
Primary contact
Prof Diederik Dippel
ORCID ID
Contact details
Erasmus MC University Medical Center Rotterdam
's-Gravendijkwal 230
PO Box 2040
Rotterdam
3000CA
Netherlands
+31 (0)10 70 43979
d.dippel@erasmusmc.nl
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
NTR1804 / NL 30557.078.10 v02
Study information
Scientific title
Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands
Acronym
MR CLEAN
Study hypothesis
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 intracranial anterior circulation occlusion.
Ethics approval
Medical Ethics Committee and Resarch Board of Erasmus MC University Medical Center
Study design
Multicenter randomized open-label treatment and blinded endpoint evaluation (PROBE design)
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Patient information sheet can be found at: http://www.mrclean-trial.org/forms.htm (Dutch)
Condition
Acute ischemic stroke, caused by intracranial proximal arterial occlusion (anterior circulation)
Intervention
Intervention arms consists of endovascular treatment by means of microcatheter guided local application of recombinant tissue plasminogen activator (rt-PA) or urokinase, and/or mechanical thrombectomy, by means of a retraction device, aspiration device, or retrievable stent.
The control arm consists of regular treatment according to current national clinical guidelines.
Intervention type
Procedure/Surgery
Phase
Drug names
Primary outcome measures
Score on the modified Rankin scale at 3 months
Secondary outcome measures
Imaging parameters:
1. 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.
2. 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.
3. 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:
1. NIHSS, including NIH supplemental motor score, 50 at 24 hours
2. NIHSS at 1 week or at discharge.
Functional outcome:
1. Score on the EQ5D at 90 days
2. Barthel index at 90 days
Overall trial start date
01/12/2010
Overall trial end date
01/01/2015
Reason abandoned
Eligibility
Participant inclusion criteria
1. A clinical diagnosis of acute stroke, with a deficit on the National Institutes of Health (NIH) stroke scale of 2 points or more
2. Computerised tomography (CT) or magnetic resonance imaging (MRI) scan ruling out intracranial hemorrhage
3. Intracranial arterial occlusion of the distal intracranial carotid artery or middle (M1/M2) or anterior (A1/A2) cerebral artery, demonstrated with Computed Tomography Angiography (CTA), magnetic resonance angiography (MRA), Digital subtraction angiography (DSA) or transcranial Doppler/duplex (TCD)
4. The possibility to start treatment within 6 hours from onset
5. Informed consent given
6. Age 18 or over
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
500
Participant exclusion criteria
General:
1. Arterial blood pressure > 185/110 mmHg
2. Blood glucose < 2.7 or > 22.2 mmol/L
3. Intravenous treatment with thrombolytic therapy in a dose exceeding 0.9 mg/kg alteplase or 90 mg
4. Intravenous treatment with thrombolytic therapy despite contra-indications, i.e. 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
For Intended mechanical thrombectomy:
Laboratory evidence of coagulation abnormalities, i.e. platelet count <40 x 109/L, activated partial thromboplastin time (APTT)>50 sec or International Normalised Ratio (INR) >3.0.
For intended intra-arterial thrombolysis:
1. Cerebral infarction in the distribution of the relevant occluded artery in the previous 6 weeks
2. History of intracerebral hemorrhage
3. Severe head injury (contusion) in the previous 4 weeks
4. Clinical or laboratory evidence of coagulation abnormalities, i.e. platelet count <90 x 109/L, APTT>50 sec or INR >1.7
Recruitment start date
01/12/2010
Recruitment end date
01/01/2015
Locations
Countries of recruitment
Netherlands
Trial participating centre
Erasmus MC University Medical Center Rotterdam
Rotterdam
3000CA
Netherlands
Sponsor information
Organisation
Dutch Heart Foundation (Netherlands)
Sponsor details
Prinses Catharina Amaliastraat 10
The Hague
2496 XD
Netherlands
+31 (0)70 31 55555
info@hartstichting.nl
Sponsor type
Charity
Website
Funders
Funder type
Charity
Funder name
Dutch Heart Foundation (Nederlandse Hartstichting) (Netherlands) ref: 2008T030
Alternative name(s)
Dutch Heart Foundation
Funding Body Type
private sector organisation
Funding Body Subtype
foundation
Location
Netherlands
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary
2014 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/25179366
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/25517348
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27302238
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/26903582
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27491736
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27421546
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27601379
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27827328
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28351963
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28389610
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28432266
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28436305
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28379802
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/29040040
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28799861
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28531910
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28404769
2018 results in: http://www.ncbi.nlm.nih.gov/pubmed/29321337
2018 results in: http://www.ncbi.nlm.nih.gov/pubmed/29365017
Publication citations
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Protocol
Fransen PS, Beumer D, Berkhemer OA, van den Berg LA, Lingsma H, van der Lugt A, van Zwam WH, van Oostenbrugge RJ, Roos YB, Majoie CB, Dippel DW, , 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, doi: 10.1186/1745-6215-15-343.
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Results
Berkhemer OA1, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators, A randomized trial of intraarterial treatment for acute ischemic stroke, N Engl J Med, 2015, 372, 1, 11-20, doi: 10.1056/NEJMoa1411587.
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Results
Yoo AJ, Berkhemer OA, Fransen PS, van den Berg LA, Beumer D, Lingsma HF, Schonewille WJ, Sprengers ME, van den Berg R, van Walderveen MA, Beenen LF, Wermer MJ, Nijeholt GJ, Boiten J, Jenniskens SF, Bot JC, Boers AM, Marquering HA, Roos YB, van Oostenbrugge RJ, Dippel DW, van der Lugt A, van Zwam WH, Majoie CB; MR CLEAN investigators, Effect of baseline Alberta Stroke Program Early CT Score on safety and efficacy of intra-arterial treatment: a subgroup analysis of a randomised phase 3 trial (MR CLEAN), Lancet Neurol, 2016, 15, 7, 685-694, doi: 10.1016/S1474-4422(16)00124-1.
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Results
Berkhemer OA, Jansen IG, Beumer D, Fransen PS, van den Berg LA, Yoo AJ, Lingsma HF, Sprengers ME, Jenniskens SF1, Lycklama À Nijeholt GJ1, van Walderveen MA1, van den Berg R1, Bot JC1, Beenen LF1, Boers AM1, Slump CH1, Roos YB1, van Oostenbrugge RJ, Dippel DW, van der Lugt A, van Zwam WH, Marquering HA, Majoie CB; MR CLEAN Investigators, Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients With Proximal Anterior Circulation Stroke, Stroke, 2016 , 47, 3, 768-776, doi: 10.1161/STROKEAHA.115.011788.
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Results
Al-Ali F, Berkhemer OA, Yousman WP, Elias JJ, Bender EN, Lingsma HF, van der Lugt A, Dippel DW, Roos YB, van Oostenbrugge RJ, van Zwam W, Dillon WP, Majoie CB, The Capillary Index Score as a Marker of Viable Cerebral Tissue: Proof of Concept-The Capillary Index Score in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Trial, Stroke, 2016, pii: STROKEAHA.116.013513, doi: 10.1161/STROKEAHA.116.013513.
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Results
Berkhemer OA, van den Berg LA, Fransen PS, Beumer D, Yoo AJ, Lingsma HF, Schonewille WJ, van den Berg R, Wermer MJ, Boiten J, Lycklama À Nijeholt GJ, Nederkoorn PJ, Hollmann MW, van Zwam WH, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW, Roos YB; MR CLEAN investigators, The effect of anesthetic management during intra-arterial therapy for acute stroke in MR CLEAN, Neurology, 2016 , 87, 7, 656-664, doi: 10.1212/WNL.0000000000002976.