Condition category
Nervous System Diseases
Date applied
31/10/2017
Date assigned
09/11/2017
Last edited
08/11/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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

http://www.mrclean-noiv.nl

Contact information

Type

Scientific

Primary contact

Prof Yvo Roos

ORCID ID

Contact details

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

Type

Scientific

Additional contact

Prof Charles Majoie

ORCID ID

Contact details

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

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

NL58320.078.17

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

Acronym

MR CLEAN-NO IV

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

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

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

Condition

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

Intervention

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

Other

Phase

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

01/05/2017

Overall trial end date

30/04/2022

Reason abandoned (if study stopped)

Eligibility

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

Patient

Age group

Adult

Gender

Both

Target number of participants

540

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

15/11/2017

Recruitment end date

14/11/2021

Locations

Countries of recruitment

Netherlands

Trial participating centre

Academic Medical Centre Amsterdam
Meibergdreef 9
Amsterdam
1105 AZ
Netherlands

Trial participating centre

Maastricht University Medical Centre
P. Debyelaan 25
Maastricht
6229 HX
Netherlands

Trial participating centre

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

Trial participating centre

University Medical Centre Utrecht
Heidelberglaan 100
Utrecht
3584 CX
Netherlands

Sponsor information

Organisation

Academic Medical Centre Amsterdam

Sponsor details

Meibergdreef 9
Amsterdam
1105 AZ Amsterdam
Netherlands
+ 31 20 5662109
secretariaatrvb@amc.nl

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Industry

Funder name

Stryker

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Hartstichting (Netherlands, Dutch Heart Foundation)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Hersenstichting (Netherlands, Dutch Brain Foundation)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

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

31/05/2023

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes