Condition category
Nervous System Diseases
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status

Plain English Summary

Background and study aims
Stroke is a major cause of death and disability. Eighty percent of stroke cases are ischemic (caused when there is a restriction in blood supply to the brain) in nature, meaning that a clot blocks a cerebral artery. In the Netherlands (16.7 million inhabitants), each year more than 20,000 individuals are admitted to hospital and up to 8500 patients die because of ischaemic stroke. Until recently, intravenous thrombolysis (IVT) with alteplase (injections to try to dissolve blood clots) was the only proven therapy for stroke. In 2015, however, studies showed that mechanical removal of the clot with a stent retriever/aspiration device (intra-arterial treatment, or IAT) improved functional outcome compared to IVT alone. However, all of these studies included patients who also received IVT, unless they had a contra-indication for IVT. Also, 67% of patients treated with IVT followed by IAT remained functionally dependent. Furthermore, the effect of IAT on functional outcome appears not to be influenced by IVT. This raises the question whether IVT is still of added benefit to stroke patients who are treated with IAT. The aim of this study is to assess whether direct IAT is more effective than IVT followed by IAT on improving functional outcome at 3 months.

Who can participate?
Adult patients with a clinical diagnosis of acute ischemic stroke and a confirmed clot in a major cerebral artery, who are eligible for IVT and IAT.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive the standard treatment, which is IVT followed by IAT. Those in the second group receive direct intra-arterial treatment. At three months, the functional outcome of both groups are measured and compared to asses which type of treatment is most effective. All patients undergo a follow-up cranial non-contrast CT scan at 5-7 days or at discharge, and three extra blood samples are taken from all patients.

What are the possible benefits and risks of participating?
There are benefits and risks with both procedures. IVT is a standard treatment, however, it is associated with bleeding complications. It might cause the clot to move to where it cannot be reached by the stent retriever. Conversely, it is an ultra-fast mode of treatment and it may help soften the clot for mechanical removal. IAT is also a standard treatment, but is associated with a slightly higher risk of infarctions in new vascular territories in treatment with IAT and groin hematomas.

Where is the study run from?
This study is being run by the Academic Medical Centre (AMC) (Netherlands).

When is the study starting and how long is it expected to run for?
May 2017 to April 2022

Who is funding the study?
Stryker (Netherlands)
Hartstichting (Netherlands, Dutch Heart Foundation)
Hersenstichting (Netherlands, Dutch Brain Foundation)

Who is the main contact?
1. Professor Yvo Roos (Scientific)
2. Professor Charles Majoie (Scientific)

Trial website

Contact information



Primary contact

Prof Yvo Roos


Contact details

Academic Medical Centre Amsterdam
Department of Neurology
PO Box 22660
1100 DD



Additional contact

Prof Charles Majoie


Contact details

Academic Medical Centre Amsterdam
Department of Radiology and Nuclear Medicine
PO box 22660
1100 DD

Additional identifiers

EudraCT number number

Protocol/serial number


Study information

Scientific title

MR CLEAN-NO IV: Intravenous treatment followed by intra-arterial treatment versus direct intra-arterial treatment for acute ischaemic stroke caused by a proximal intracranial occlusion



Study hypothesis

Direct intra-arterial treatment will lead to a better functional outcome compared to intravenous thrombolysis with alteplase followed by intra-arterial treatment in patients with acute ischaemic stroke based on a large vessel occlusion.

Ethics approval

Medical Ethics Committee Erasmus MC University Medical Centre Rotterdam, 19-10-2017, ref: MEC-2017-368.

Study design

Multicentre phase III prospective randomised clinical trial with open-label treatment and blinded outcome assessment (PROBE).

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.


Acute ischaemic stroke based on an intracranial large vessel occlusion of the anterior circulation.


Participants are randomly allocated using acomputer- and web-based programme, using permuted blocks, to receiving either direct intra-arterial treatment, or intravenous thrombolysis with alteplase followed by intra-arterial treatment. Back-up by telephone is provided. Randomisation is allowed when the occlusion has been established by CTA or MRA and isstratified by center and inclusion in the active treatment arm of the MR ASAP trial (Multicentre randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch: pre-hospital augmentation of collateral blood flow and blood pressure reduction).

Intra-arterial treatment involves catheterisation, after which intracranial thrombectomy is performed with a stent-retriever or other device approved by the steering committee. Every participant undergoes a CTA of the cerebral vessels to assess rate of recanalisation at 24 hours after randomisation, and a cranial non-contrast CT to assess final infarct volume 5-7 days after randomisation. Three months after inclusion, all participants are interviewed by telephone to determine functional outcome.

Intervention type



Drug names

Primary outcome measure

Functional outcome measured by the score on the modified Rankin Scale (mRS) at 90 days.

Secondary outcome measures

1. Death, defined as a score of 6 on the mRS, within 90 days (± 14 days)
2. Pre-interventional recanalisation, defined as an extended treatment in cerebral ischaemia(eTICI) score of 2b or more on first angiography
3. Reperfusion as measured by an eTICI score of 2b or more on final angiography of IAT
4. Recanalisation rate assessed with CT-angiography at 24 hours
5. Clinical stroke severity, measured by the National Institutes of Health Stroke Scale score at 24 hours and 5-7 days, or at discharge
6. Final infarct volume measured on cranial non-contrast CT at 5-7 days after randomisation
7. Dichotomised clinical outcome on the mRS at 90 days
8. Quality of life as measured on the EQ5D-5L at 90 days (± 14 days)
9. Functional independence as measured by the Barthel index at 90 days (± 14 days)

Safety outcome measures
1. Hemorrhages according to the Heidelberg criteria
2. Symptomatic intracerebral hemorrhages, according to the Heidelberg criteria
3. Embolisation in new territory on angiography during IAT
4. Occurrence of aneurysma spurium
5. Occurrence of groin haematoma
6. Infarction in a new territory on cranial non-contrast CT at 5-7 days
7. Death from all causes within 90 days (± 14 days).

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

1. A clinical diagnosis of acute ischaemic stroke
2. Caused by a large vessel occlusion of the anterior circulation (distal intracranial
3. Carotid artery or middle (M1/proximal M2) cerebral artery confirmed by neuroimaging
(CTA or MRA)
4. CT or MRI ruling out intracranial hemorrhage
5. Eligible for IVT (within 4.5 hours after symptom onset)
6. Ascore of at least 2 on the NIH Stroke Scale
7. Age of 18 years or older
8. Written informed consent (deferred)

Participant type


Age group




Target number of participants


Participant exclusion criteria

1. Pre-stroke disability which interferes with the assessment of functional outcome at 90 days
i.e. mRS >2
2. Participation in trials other than current and MR ASAP
3. Any contra-indication for IVT, according to national guidelines, which are in accordance with guidelines of the American Heart Association, i.e.:
3.1. Arterial blood pressure exceeding 185/110 mmHg
3.2. Blood glucose less than 2.7 or over 22.2 mmol/L
3.3. Cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuro-imaging
3.4. Recent head trauma
3.5. Recent major surgery or serious trauma
3.6. Recent gastrointestinal or urinary tract hemorrhage
3.7. Previous intracerebral hemorrhage
3.8. Use of anticoagulant with INR exceeding 1.7
3.9. Known thrombocyte count less than 100 x 109/L
3.10. Treatment with direct thrombin or factor X inhibitors
3.11. Treatment with therapeutic dose of (low-molecular weight) heparin

Recruitment start date


Recruitment end date



Countries of recruitment


Trial participating centre

Academic Medical Centre Amsterdam
Meibergdreef 9
1105 AZ

Trial participating centre

Maastricht University Medical Centre
P. Debyelaan 25
6229 HX

Trial participating centre

Erasmus MC University Medical Centre Rotterdam
's-Gravendijkwal 230
3000 CA

Trial participating centre

University Medical Centre Utrecht
Heidelberglaan 100
3584 CX

Sponsor information


Academic Medical Centre Amsterdam

Sponsor details

Meibergdreef 9
1105 AZ Amsterdam
+ 31 20 5662109

Sponsor type

Hospital/treatment centre



Funder type


Funder name


Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

Hartstichting (Netherlands, Dutch Heart Foundation)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

Hersenstichting (Netherlands, Dutch Brain Foundation)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Results and Publications

Publication and dissemination plan

Planned publication in a high impact peer reviewed journal, intent to publish within one year after the overall trial end date. A study protocol and statistical analysis plan will be available once published.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date


Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

16/07/2019: Internal review.