News and upcoming events
The last MR CLEAN NO IV patient has just been randomized
With 540 included patients in total, the end of the trial's inclusion period has been reached - almost six months ahead of schedule! The randomization program will now be closed, so from now on no further patients can be randomized.
We are incredibly proud and happy with this milestone, but above all, we are grateful to all centers for all their inclusions and invaluable efforts!
Final interim analysis results
On June 30, the final MR CLEAN NO IV interim analysis took place, including data of the first 400 included patients. The DSMB advised to continue inclusions, up to the final sample size of 540 patients. The main point of focus for these last months should be to lower door-to-groin puncture times. We will continue inclusions - only 83 patients to go - and want to thank all investigators and participating centers!
Results of DIRECT-MT now online at www.NEJM.org
DIRECT MT is the first RCT clearly demonstrating that mechanical thrombectomy alone using stent retrievers is essentially equivalent to mechanical thrombectomy preceded by iv alteplase in acute ischemic stroke patients with an intracranial large vessel occlusion presenting at a comprehensive stroke center.
This high quality trial will change the landscape of acute ischemic stroke treatment globally, certainly when results are confirmed with other ongoing trials evaluating EVT alone with EVT preceded by IV alteplase (MRCLEAN NO-IV, SWIFT-DIRECT, DIRECT-SAFE and SKIP).
We would like to congratulate the DIRECT-MT investigators in China, in particular Professors Jianmin Liu and Pengfei Yang, with the results and the unprecedented highly efficient and successful execution of the trial, with inclusion of the 656 patients in 20 months in 41 centers all over China!
2nd interim analysis results
On January 15, our second large interim analysis took place, including the first 250 randomized patients. All centers worked hard to complete the data as fully as possible - for which we first and foremost want to thank all participating centers and investigators!
The DSMB advised to continue including patients as fast as possible: which means we will continue on to the next landmark of 400 patients. Hereby, we will give you a brief summary of the points of attention that the DSMB noted, and that need our attention during the last months of the trial.
- Blood pressure at randomization. As you may know, the maximum blood pressure to be eligible for IVT is 180/110 mmHg. There is a high number of patients right now for whom a blood pressure above that limit is entered: 30 (9.4%) to be exact. Possibly, a measurement before or after the correct blood pressure at randomization was entered; blood pressure may of course vary in the acute phase of stroke. We will check discharge letters, and contact centers if we cannot find any additional data there.
- DSA images. To assess pre-IAT eTICI (effect of IVT) and final eTICI scores, anteroposterior and lateral runs are needed before and after thrombectomy. We regularly send feedback of received images to the center's research nurses and radiological PI's, tab 2 shows the DSA quality summary in these. For centers who have not sent in any imaging yet: we will get in touch with you over the upcoming weeks.
- Non-EVT eligible randomizations. Because of the acute nature of the trial, it can occur that a randomized patient does not undergo thrombectomy after all. We do take these patients into the intention to treat analysis, since excluding them would result in risking a bias. Please remember to ask consent (for participation or only data usage) and/or perform follow-up imaging if possible.
In May this year, many of us will meet at the ESO/WSO conference 2020 in Vienna, Austria. Like last year, we will organize an Investigator's Meeting for all investigators.
Finally, last but not least: we are approaching our 400th inclusion! Three months after this landmark, our very last interim analysis will take place. This will probably be in June/July of this year. We would like to encourage everyone to complete the OpenClinica data, send in the imaging and discharge letters as early as possible, to prevent any pre-summer stress. Of course, completion overviews will follow (with the 'startup flaws' eliminated thanks to your feedback and Olvert's work).
We are very happy with how the trial is running, with all its challenges encountered underway. When compared to the parallel trials SKIP (Japan, low-dose thrombolysis, presented at ISC2020) and DIRECT-MT (China, presented at ESO/WSO 2020), as well as SWIFT-DIRECT (Switzerland, now running) and DIRECT SAFE (Australia, now running), the NO IV collaboration is truly unique, inclusions are going really fast, and data collection is quick, high-quality, and relatively uncomplicated. This is seen and valued; we hope to continue this way on to the very last inclusion this fall!
200th MR CLEAN NO IV patient included
The Isala Hospital in Zwolle included the 200th patient in the MR CLEAN NO IV. We would like to thank all centers for their inclusions and efforts!
ESOC 2019: NO IV Investigator’s meeting
During this year’s ESOC in Milan, we hosted a meeting for all participating investigators to provide an update and discuss the progress of the trial. We are very pleased with the progress thus far and would like to thank all investigators for their time and effort. Below, you will find a brief summary and a selection of photos. We hope to see everyone at ESOC 2020 in Vienna!
- Current number of inclusions: 194
- Speed of inclusion: 20-25/month
- Actively including centers: 14
- 1st interim analysis: June 6th
- Parallel trials: DIRECT-MT (China), SWIFT DIRECT (Switzerland/Europe, Canada),DIRECT SAFE (Australia), SKIP (Japan). Agreements for individual patient data pooling to enable dequate investigation of subgroups have been made with the DIRECT-MT trial, and are being discussed with the other trials. We hope to enable a joint analysis and close collaboration.
- Deferred consent: shortens time to treatment, although may contribute to randomization of patients that are actually ineligible.
- Randomization errors: so far, 6 patients were randomized though they turned out to be ineligible for endovascular thrombectomy (EVT). These patients are included in the intention-to-treat analysis, so their consent and follow-up imaging is required. They will be excluded from the per-protocol analysis. Several tips were exchanged to diminish the chance of ‘ineligible’ randomization –for example, calling the neuro-interventionalist in advance to assess CTA imaging of a possible EVT candidate, to quickly determine EVT eligibility.
- Treatment times: door to needle times increased slightly in centers (ca. 5 minutes) due to CTA assessment for EVT eligibility before administering intravenous thrombolysis (IVT). Compared to international benchmarks, median door to needle times in the NO IV trial are still low.Median door to groin times are below the desired maximum of 60 minutes. There is some variation between centers and patients.
- Choice of device: the current protocol states that the first-line treatment modality during EVT must be a stent-retriever. However, an increasing number of trials suggesting non-inferiority of aspiration as first line of defense is published (ASTER, COMPASS, ASTER-2 presented at this year’s ESOC). The steering committee will discuss the possibility to leave the device choice to the treating interventionalist.
- DSA: important secondary and safety outcomes of the NO IV trial can only be assessed on DSA. These outcomes include pre-interventional recanalization, successful reperfusion by EVT, and embolization in new territory during EVT. DSA images should contain:
- pre-EVT series with AP and lateral directions, complete up to the venous phase, and
- post-EVT series with AP and lateral directions, complete up to the venous phase.
- Follow-up imaging: also necessary to determine secondary (recanalization rate, final infarct volume), and safety outcomes (infarct in new territory). Complete follow-up imaging consists of 24-48-hour MRI (FLAIR, DWI, T2*, 3D TOF) or 24+/-12 hour NCCT and CTA plus 5-7 days/discharge NCCT. Automatic assessment tools such as final infarct volume measurement are being developed now, and will be used in the assessments of the trial images.
- Imaging SOPs can be found on: https://www.contrast-consortium.nl/work-packagesinfo-2/wp7-imaging-data-management/
For the full presentation slides, click here.
Finally and most importantly, we would once again like to emphasize our appreciation for and recognition of everyone’s great efforts for the data collection, discussions and communication about complex cases, thinking about solutions, and suggestions on how to move forward. All trial nurses, PI’s, PhD students, research assistants, residents, doctors, technicians – thank you, we hope to continue the promising progress made so far!
ESOC 2019: MR CLEAN NO IV poster presentation
The progress of the MR CLEAN NO IV trial was presented as a poster during this year’s ESOC in Milan, by trial PhDs Natalie LeCouffe, Kilian Treurniet, and Manon Kappelhof. We were pleased to discuss the challenges and achievements of the trial so far, and are looking forward to our next poster presentation at the CONTRAST consortium meeting in Groningen, June 12th.