Closed trials
MR CLEAN NOIV
The MR CLEAN-NO IV trial is a Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands investigating the added benefit of intravenous alteplase prior to intra-arterial thrombectomy in stroke patients with an intracranial occlusion of the anterior circulation.
Final patient included in the MR CLEAN NOIV
On the 28th of Oktober 2020, the final patient (with registered consent) was included in the MR CLEAN NO IV trial.
Results of the MR CLEAN-NO IV trial have been published in the New England Journal of Medicine on November 11, 2021: https://www.nejm.org/doi/full/10.1056/NEJMoa2107727.
Kind regards,
MR CLEAN-NO IV executive committee on behalf of the CONTRAST consortium:
Yvo Roos,
Charles Majoie,
MR CLEAN-NO IV principal investigators
MR CLEAN NOIV Rationale and aim
Since the publication of five large randomized controlled trials in 2015, intra-arterial treatment (IAT) by means of a stent retriever has become standard of care for patients with acute ischemic stroke due to an intracranial large vessel occlusion of the anterior circulation. Up until then, however, intravenous thrombolysis with alteplase (IVT) was the only proven reperfusion therapy for patients with acute ischemic stroke. Therefore the patients included in these trials also underwent IVT, unless contraindicated.
Currently it is unclear whether IVT is still of benefit to patients with a large vessel occlusion. Potential advantages include early recanalization, fewer required passes with a stent retriever, improved microvascular reperfusion and lysis of distal emboli. Potential disadvantages include low recanalization rates in large vessel occlusions, hemorrhagic complications, delay to treatment with IAT, thrombus fragmentation and neurotoxicity of alteplase itself.
The primary aim of the MR CLEAN-NO IV trial is to assess the effect of direct IAT compared with IVT followed by IAT on functional outcome in patients with acute ischemic stroke, caused by an anterior circulation occlusion that is confirmed by neuro-imaging.
MR CLEAN NOIV Organization
The MR CLEAN-NO IV trial will be conducted by members of the CONTRAST consortium.
Principle investigators:
Prof. dr. Yvo Roos, neurologist, Academic Medical Center Amsterdam
Prof. dr. Charles Majoie, interventional neuroradiologist, Academic Medical Center Amsterdam
Coordinating investigators:
Dr. Jonathan Coutinho, neurologist, Academic Medical Center Amsterdam
Dr. Bart Emmer, interventional neuroradiologist, Academic Medical Center Amsterdam
Natalie LeCouffe, PhD student (department of neurology), Academic Medical Center Amsterdam
Kilian Treurniet, PhD student (department of radiology), Academic Medical Center Amsterdam
Manon Kappelhof, PhD student (department of radiology), Academic Medical Center Amsterdam
Leon Rinkel, PhD student (department of neurology), Academic Medical Center Amsterdam
Executive committee:
Prof. dr. Yvo Roos, neurologist, AMC
Prof. dr. Charles Majoie, interventional neuroradiologist AMC
Dr. Jonathan Coutinho, neurologist, AMC
Prof. dr. Diederik Dippel, neurologist, Erasmus MC
Dr. Adriaan van Es, interventional neuroradiologist, Erasmus MC
Dr. Bart Emmer, interventional neuroradiologist, AMC
Dr. Jelis Boiten, neurologist, HMC
Dr. Geert Lycklama, interventional neuroradiologist, HMC
Dr. Koos Keizer, neurologist, Catharina Zh
Drs. Lonneke Yo, interventional radiologist, Catharina Zh
Dr. Wim van Zwam, interventional radiologist, MUMC
Steering committee:
To be announced.
MR CLEAN NOIV Study design
Design
The MR CLEAN-NO IV trial is a phase III prospective randomized clinical trial with open-label treatment and blinded outcome assessment (PROBE). The study will run for 4 years in multiple intervention centers in Europe.
Population
The study population will consist of adult patients who meet the following inclusion criteria:
| Inclusion criteria |
| a clinical diagnosis of acute ischemic stroke |
| caused by a large vessel occlusion of the anterior circulation (distal intracranial carotid artery or middle (M1/proximal M2) cerebral artery confirmed by neuro imaging (CTA or MRA) |
| CT or MRI ruling out intracranial hemorrhage |
| eligible for IVT (within 4.5 hours after symptom onset) |
| a score of at least 2 on the NIH Stroke Scale |
| age of 18 years or older |
| written informed consent (deferred) |
A potential subject who meets any of the following criteria will be excluded from participation in this study:
| Exclusion criteria |
| Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS >2 |
| Participation in trials other than current (or MR ASAP for participating centers in the Netherlands) |
| Any contra-indication for IVT, according to national guidelines, which are in accordance with guidelines of the American Heart Association, i.e.: o arterial blood pressure exceeding 185/110 mmHg o blood glucose less than 2.7 or over 22.2 mmol/L o cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuro-imaging o recent head trauma o recent major surgery or serious trauma o recent gastrointestinal or urinary tract hemorrhage o previous intracerebral hemorrhage o use of anticoagulant with INR exceeding 1.7 o known thrombocyte count less than 100 x 109/L o treatment with direct thrombin or factor X inhibitors o treatment with therapeutic dose of (low-molecular weight) heparin. |
Inclusion in other intervention trials during the study period is not allowed. Note that preceding inclusion in the Multicenter Randomized trial of Acute Stroke Treatment with a nitroglycerine patch (MR ASAP) is not an exclusion criterion for participating centers in the Netherlands.
Randomization
Patients will be randomly allocated to IVT followed by IAT (standard care) or direct IAT by a computer- and web-based procedure.
Primary outcome
The main study outcome is functional outcome at 90 days (± 14 days) as measured on the modified Rankin Scale score.
Informed consent
This study evaluates the influence of an acute treatment in an emergency situation concerning a life-threatening disorder. For every hour delay, the absolute benefit of treatment (probability or recovery to independent living) decreases by 6%. Treatment should therefore be started as soon as possible. Since most patients with acute neurological deficits are not capable of decision making, and to reduce treatment delays, the MR CLEAN-NO IV trial uses a deferred informed consent procedure, in line with Dutch law (Dutch Medical Research (Human Subjects) Act: 6,4). This implicates that patients are randomized and treated before consent is obtained. Written informed consent should be obtained within 24 hours after enrolment. This was approved by the Medical Ethics Committee of the Erasmus University Medical Center Rotterdam.
MR CLEAN NOIV Trial progress
MR CLEAN NOIV Contact
Coordinating Investigators
Dr. Jonathan Coutinho, neurologist
Department of Neurology
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
Dr. Bart Emmer, interventional neuroradiologist
Department of Radiology and Nuclear Medicine
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
Natalie LeCouffe, PhD candidate
Department of Neurology
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
Kilian Treurniet, PhD candidate
Department of Radiology and Nuclear Medicine
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
Email: mrclean-noiv@amc.nl
Telephone: 0031 20 566 3547/ 0031 20 5662432 (office hours)
Chief Investigators
Prof. dr. Yvo Roos, neurologist
Department of Neurology
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
Telephone: 0031 20 566 3942
Prof. dr. Charles Majoie, interventional neuroradiologist
Department of Radiology and Nuclear Medicine,
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
Telephone: 0031 20 566 3409
Long-term follow-up phase of MR CLEAN-NO IV
Dr. Maarten Uyttenboogaart
Afdeling Neurologie, UMC Groningen
Telephone: 050-361142
Dr. Maarten M.H. Lahr
Afdeling Epidemiologie
Mw. Rita Sprengers
Klinisch Onderzoeksbureau Neurologie
Amsterdam UMC, locatie AMC
Telephone: 020-5664062
E-mail: noiv-followup@amsterdamumc.nl
MR CLEAN NOIV IRIS
IRIS: Improving Reperfusion strategies for Ischemic Stroke
Individual patient data pooled meta-analysis of six randomized controlled trials on the value of intravenous recombinant tissue plasminogen activator (rtPA) administration prior to endovascular treatment (EVT), for acute ischemic stroke caused by anterior circulation large vessel occlusions.
The trial team of MR CLEAN-NO IV is collaborating with the trial teams of DIRECT-SAFE, DEVT, DIRECT-MT, SKIP, and SWIFT DIRECT on an individual patient data pooled meta-analysis, in order to achieve the most accurate estimate of the value of intravenous rtPA prior to EVT. Further updates on this follow-up project of the MR CLEAN-NO IV trial will be posted on this webpage, in addition to the News page.
IRIS Statistical Analysis Plan
IRIS Principal Investigators, per participating trial team
DIRECT-MT:
Prof. Jianmin Liu, MD, PhD, Changhai Hospital, China
Prof. Pengfei Yang, MD, PhD, Changhai Hospital, China
Prof. Yongwei Zhang, MD, PhD, Changhai Hospital, China
DEVT:
Prof. Wenjie Zi, MD, Xinqiao Hospital, China
Prof. Raul Nogueira, MD, Emory University School of Medicine, Georgia, USA
Qingwu Yang, MD, PhD, Xinqiao Hospital, China
SKIP:
Prof. Kentaro Suzuki, MD, PhD, Nippon Medical School Tokyo, Japan
Prof. Kazumi Kimura, MD, PhD, Nippon Medical School Tokyo, Japan
Yuji Matsumaru, MD, PhD, University of Tsakuba, Ibaraki, Japan
DIRECT-SAFE:
Prof. Bernard Yan, MD, PhD, The Royal Melbourne Hospital, Australia
Prof. Peter Mitchell, MD, PhD, The Royal Melbourne Hospital, Australia
Zhongrong Miao, MD, The Royal Melbourne Hospital, Australia
SWIFT DIRECT:
Prof. Urs Fischer, MD, PhD, Universitätsspital Basel, Switzerland
Prof. Jan Gralla, Inselspital Bern, Switzerland
Johannes Kaesmacher, MD PhD, Inselspital Bern, Switzerland
MR CLEAN-NO IV:
Prof. Charles Majoie, MD, PhD, Amsterdam UMC, the Netherlands
Prof. Yvo Roos, MD, PhD, Amsterdam UMC, the Netherlands
Kilian Treurniet, MD, PhD, Amsterdam UMC, the Netherlands
Manon Kappelhof, MD, PhD, Amsterdam UMC, the Netherlands
Fabiano Cavalcante, MD, Amsterdam UMC, the Netherlands
Data and Imaging committee
Steven Bush, MD, The Royal Melbourne Hospital, Australia
Lei Zhang, MD, Changhai Hospital, China
Prof. Kentaro Suzuki, MD, PhD, Nippon Medical School Tokyo, Japan
Prof. Jan Gralla, Inselspital Bern, Switzerland
Prof. Urs Fischer, MD, PhD, Universitätsspital Basel, Switzerland
Johannes Kaesmacher, MD PhD, Inselspital Bern, Switzerland
Prof. Charles Majoie, MD, PhD, Amsterdam UMC, the Netherlands
Kilian Treurniet, MD, PhD, Amsterdam UMC, the Netherlands
Manon Kappelhof, MD, PhD, Amsterdam UMC, the Netherlands
Fabiano Cavalcante, MD, Amsterdam UMC, the Netherlands
Statisticians
Prof. Hester Lingsma, PhD, Erasmus MC, the Netherlands
Prof. Leonid Churilov, PhD, University of Melbourne, Australia
Daan Nieboer, PhD, Erasmus MC, the Netherlands
Contact
Fabiano Cavalcante, PhD candidate/neurologist, f.cavalcante@amsterdamumc.nl
Manon Kappelhof, postdoc/Radiology resident, m.kappelhof@amsterdamumc.nl
Kilian Treurniet, postdoc/Radiology resident, k.m.treurniet@amsterdamumc.nl