Is intravenous alteplase still of added benefit in patients with acute ischaemic stroke who undergo intra-arterial treatment?
| ISRCTN | ISRCTN80619088 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN80619088 |
| Secondary identifying numbers | NL58320.078.17 |
- Submission date
- 31/10/2017
- Registration date
- 09/11/2017
- Last edited
- 29/08/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
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 February 2021
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)
Contact information
Scientific
Academic Medical Centre Amsterdam
Department of Neurology
PO Box 22660
Amsterdam
1100 DD
Netherlands
Scientific
Academic Medical Centre Amsterdam
Department of Radiology and Nuclear Medicine
PO box 22660
Amsterdam
1100 DD
Netherlands
Study information
| 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 |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet. |
| 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 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(s) | Medical Ethics Committee Erasmus MC University Medical Centre Rotterdam, 19-10-2017, ref: MEC-2017-368. |
| 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 |
| 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 study start date | 01/05/2017 |
| Overall study end date | 05/02/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 540 |
| Total final enrolment | 539 |
| 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 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 | 24/01/2018 |
| Recruitment end date | 28/10/2020 |
Locations
Countries of recruitment
- Belgium
- France
- Netherlands
Study participating centres
Amsterdam
1105 AZ
Netherlands
Maastricht
6229 HX
Netherlands
Rotterdam
3000 CA
Netherlands
Utrecht
3584 CX
Netherlands
Sponsor information
Hospital/treatment centre
Meibergdreef 9
Amsterdam
1105 AZ Amsterdam
Netherlands
| Phone | + 31 20 5662109 |
|---|---|
| secretariaatrvb@amc.nl |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Stryker Corporation
- Location
- United States of America
No information available
No information available
Results and Publications
| Intention to publish date | 11/11/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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 plan | The de-identified dataset generated during and/or analysed during the current study will be available upon request through www.contrast-consortium.nl/data-request-form/ from 18 months after the trial publication date until 15 years after publication. The data will be made available to researchers who are CONTRAST consortium members or collaborators, and whose proposed use of the data has been approved by the CONTRAST data access and writing committee. The data will only be made available for specified purposes, as defined in the sub-study proposal and approved by the CONTRAST data access and writing committee. To ensure transparency and quality, researchers should adhere to the CONTRAST publication policy, accessible on https://www.contrast-consortium.nl/publication-policy-contrast/. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Statistical Analysis Plan | version V1.0 | 22/10/2020 | 23/11/2020 | No | No |
| Statistical Analysis Plan | version V2.0 | 16/01/2021 | 18/01/2021 | No | No |
| Protocol article | protocol | 07/01/2020 | 16/02/2021 | Yes | No |
| Results article | 01/07/2020 | 14/04/2021 | Yes | No | |
| Results article | 11/11/2021 | 11/11/2021 | Yes | No | |
| Results article | 13/07/2022 | 14/07/2022 | Yes | No | |
| Other publications | Post hoc analysis of association between outcomes in patients with high systolic blood pressure and prior intravenous thrombolysis | 29/08/2023 | Yes | No |
Additional files
- ISRCTN80619088_SAP_V1.0_22Oct20.pdf
- Uploaded 23/11/2020
- ISRCTN80619088_SAP_V2.0_16Jan2021.pdf
- Uploaded 18/01/2021
Editorial Notes
29/08/2023: Publication reference added.
14/07/2022: Publication reference added.
21/04/2022: The following changes have been made:
1. The overall trial end date has been changed from 30/04/2022 to 05/02/2021 and the plain English summary has been updated to reflect this change.
2. The intention to publish date has been changed from 01/06/2021 to 11/11/2021.
3. The total final enrolment number has been changed from 680 to 539.
4. The individual participant data (IPD) sharing statement has been updated and the IPD sharing summary has been changed from "Data sharing statement to be made available at a later date" to "Available on request".
11/11/2021: Publication reference added.
14/04/2021: The following changes were made to the trial record:
1. Publication reference added.
2. The total final enrolment was added.
16/02/2021: Publication reference added.
18/01/2021: Uploaded statistical analysis plan.
23/11/2020: The following changes were made to the trial record:
1. The recruitment start date was changed from 15/11/2017 to 24/01/2018.
2. The recruitment end date was changed from 14/11/2021 to 28/10/2020.
3. The intention to publish date was changed from 31/05/2023 to 01/06/2021.
4. Haaglanden Medical Center, Catharina Hospital, Rijnstate Hospital, University Medical Center Groningen, Amphia Hospital, Isala Hospital, Radboud University Medical Center, Antonius Hospital, Haga Hospital, Albert Schweitzer Hospital, Elisabeth-Tweesteden Hospital, Medisch Spectrum Twente, CHU Montpellier, Hôpital de la Salpêtrière, UZ Leuven, CHU de Liège were added to the trial participating centres.
5. Belgium and France were added to the countries of recruitment.
6. Uploaded statistical analysis plan.
16/07/2019: Internal review.
