MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial

KM Treurniet; NE LeCouffe; M Kappelhof; BJ Emmer; A van Es; J Boiten; G J Lycklama; K Keizer; LSF Yo; Hester Lingsma; WH Zwam; I Ridder; RJ van Oostenbrugge; Aad van der Lugt; Diederik Dippel; J M Coutinho; Y Roos; C Majoie

doi:10.1186/s13063-021-05063-5

MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial

KM Treurniet, NE LeCouffe, M Kappelhof, BJ Emmer, A van Es, J Boiten, G J Lycklama, K Keizer, LSF Yo, Hester Lingsma, WH Zwam, I Ridder, RJ van Oostenbrugge, Aad van der Lugt, Diederik Dippel, J M Coutinho, Y Roos, C Majoie

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Abstract

Background: Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO. Methods: MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included. Discussion: IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT. Trial registration: www.isrctn.com: ISRCTN80619088. Registered on 31 October 2017.

Original language	English
Article number	141
Journal	Trials
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s13063-021-05063-5
Publication status	Published - 15 Feb 2021

Bibliographical note

Funding Information:
DD and AvdL report that Erasmus MC received research grants from Dutch Heart Foundation, Dutch Brain Foundation, AngioCare BV, Covidien/EV3®, MEDAC Gmbh/LAMEPRO, Penumbra Inc., Stryker, and Top Medical/Concentric, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, Stryker, Thrombolytic Science, LLC, and Cerenovus.

Funding Information:
We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health~Holland, Top Sector Life Sciences & Health (LSHM17016) of Medtronic and Cerenovus. Amsterdam UMC, location AMC, and Erasmus MC received additional unrestricted funding on behalf of CONTRAST, for the execution of MR CLEAN-NO IV of Stryker. We acknowledge the contributions of the MR CLEAN-NO IV Investigators. A full list of all Investigators can be found in Additional file 1. Amsterdam UMC, location AMC, Meibergdreef 9, 1105AZ, the Netherlands. The sponsor has an insurance, which is in accordance with legal requirements in the Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects through injury or death caused by the study.

Funding Information:
We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health~Holland, Top Sector Life Sciences & Health (LSHM17016) of Medtronic and Cerenovus. Amsterdam UMC, location AMC, and Erasmus MC received additional unrestricted funding on behalf of CONTRAST, for the execution of MR CLEAN-NO IV of Stryker.

Funding Information:
MR CLEAN-NO IV is executed within the CONTRAST consortium. The CONTRAST consortium is supported by Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation, by the Brain Foundation Netherlands and powered by Health~Holland, Top Sector Life Sciences, and receives unrestricted funding from Medtronic and Cerenovus. CONTRAST is funded by a Cardiovascular Research the Netherlands (CVON) grant of the Dutch Heart Foundation, the Dutch brain foundation and industry partners. For MR CLEAN-NO IV, the consortium received an unrestricted grant from Stryker. The study is designed and will be conducted, analyzed, and interpreted by the investigators independently of the funders and sponsor. They will not have a role in writing the report and decision to submit for publication.

Publisher Copyright:
© 2021, The Author(s).

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Treurniet, KM., LeCouffe, NE., Kappelhof, M., Emmer, BJ., van Es, A., Boiten, J., Lycklama, G. J., Keizer, K., Yo, LSF., Lingsma, H., Zwam, WH., Ridder, I., van Oostenbrugge, RJ., van der Lugt, A., Dippel, D., Coutinho, J. M., Roos, Y., & Majoie, C. (2021). MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial. Trials, 22(1), Article 141. https://doi.org/10.1186/s13063-021-05063-5

@article{72a6985aa32a425a831935961de1ae8e,

title = "MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial",

abstract = "Background: Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO. Methods: MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included. Discussion: IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT. Trial registration: www.isrctn.com: ISRCTN80619088. Registered on 31 October 2017.",

author = "KM Treurniet and NE LeCouffe and M Kappelhof and BJ Emmer and {van Es}, A and J Boiten and Lycklama, {G J} and K Keizer and LSF Yo and Hester Lingsma and WH Zwam and I Ridder and {van Oostenbrugge}, RJ and {van der Lugt}, Aad and Diederik Dippel and Coutinho, {J M} and Y Roos and C Majoie",

note = "Funding Information: DD and AvdL report that Erasmus MC received research grants from Dutch Heart Foundation, Dutch Brain Foundation, AngioCare BV, Covidien/EV3{\textregistered}, MEDAC Gmbh/LAMEPRO, Penumbra Inc., Stryker, and Top Medical/Concentric, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, Stryker, Thrombolytic Science, LLC, and Cerenovus. Funding Information: We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health~Holland, Top Sector Life Sciences & Health (LSHM17016) of Medtronic and Cerenovus. Amsterdam UMC, location AMC, and Erasmus MC received additional unrestricted funding on behalf of CONTRAST, for the execution of MR CLEAN-NO IV of Stryker. We acknowledge the contributions of the MR CLEAN-NO IV Investigators. A full list of all Investigators can be found in Additional file 1. Amsterdam UMC, location AMC, Meibergdreef 9, 1105AZ, the Netherlands. The sponsor has an insurance, which is in accordance with legal requirements in the Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects through injury or death caused by the study. Funding Information: We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health~Holland, Top Sector Life Sciences & Health (LSHM17016) of Medtronic and Cerenovus. Amsterdam UMC, location AMC, and Erasmus MC received additional unrestricted funding on behalf of CONTRAST, for the execution of MR CLEAN-NO IV of Stryker. Funding Information: MR CLEAN-NO IV is executed within the CONTRAST consortium. The CONTRAST consortium is supported by Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation, by the Brain Foundation Netherlands and powered by Health~Holland, Top Sector Life Sciences, and receives unrestricted funding from Medtronic and Cerenovus. CONTRAST is funded by a Cardiovascular Research the Netherlands (CVON) grant of the Dutch Heart Foundation, the Dutch brain foundation and industry partners. For MR CLEAN-NO IV, the consortium received an unrestricted grant from Stryker. The study is designed and will be conducted, analyzed, and interpreted by the investigators independently of the funders and sponsor. They will not have a role in writing the report and decision to submit for publication. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = feb,

day = "15",

doi = "10.1186/s13063-021-05063-5",

language = "English",

volume = "22",

journal = "Trials",

issn = "1745-6215",

publisher = "BioMed Central Ltd.",

number = "1",

}

Treurniet, KM, LeCouffe, NE, Kappelhof, M, Emmer, BJ, van Es, A, Boiten, J, Lycklama, GJ, Keizer, K, Yo, LSF, Lingsma, H, Zwam, WH, Ridder, I, van Oostenbrugge, RJ, van der Lugt, A , Dippel, D, Coutinho, JM, Roos, Y & Majoie, C 2021, 'MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial', Trials, vol. 22, no. 1, 141. https://doi.org/10.1186/s13063-021-05063-5

MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial. / Treurniet, KM; LeCouffe, NE; Kappelhof, M et al.
In: Trials, Vol. 22, No. 1, 141, 15.02.2021.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial

AU - Treurniet, KM

AU - LeCouffe, NE

AU - Kappelhof, M

AU - Emmer, BJ

AU - van Es, A

AU - Boiten, J

AU - Lycklama, G J

AU - Keizer, K

AU - Yo, LSF

AU - Lingsma, Hester

AU - Zwam, WH

AU - Ridder, I

AU - van Oostenbrugge, RJ

AU - van der Lugt, Aad

AU - Dippel, Diederik

AU - Coutinho, J M

AU - Roos, Y

AU - Majoie, C

N1 - Funding Information: DD and AvdL report that Erasmus MC received research grants from Dutch Heart Foundation, Dutch Brain Foundation, AngioCare BV, Covidien/EV3®, MEDAC Gmbh/LAMEPRO, Penumbra Inc., Stryker, and Top Medical/Concentric, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, Stryker, Thrombolytic Science, LLC, and Cerenovus. Funding Information: We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health~Holland, Top Sector Life Sciences & Health (LSHM17016) of Medtronic and Cerenovus. Amsterdam UMC, location AMC, and Erasmus MC received additional unrestricted funding on behalf of CONTRAST, for the execution of MR CLEAN-NO IV of Stryker. We acknowledge the contributions of the MR CLEAN-NO IV Investigators. A full list of all Investigators can be found in Additional file 1. Amsterdam UMC, location AMC, Meibergdreef 9, 1105AZ, the Netherlands. The sponsor has an insurance, which is in accordance with legal requirements in the Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects through injury or death caused by the study. Funding Information: We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health~Holland, Top Sector Life Sciences & Health (LSHM17016) of Medtronic and Cerenovus. Amsterdam UMC, location AMC, and Erasmus MC received additional unrestricted funding on behalf of CONTRAST, for the execution of MR CLEAN-NO IV of Stryker. Funding Information: MR CLEAN-NO IV is executed within the CONTRAST consortium. The CONTRAST consortium is supported by Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation, by the Brain Foundation Netherlands and powered by Health~Holland, Top Sector Life Sciences, and receives unrestricted funding from Medtronic and Cerenovus. CONTRAST is funded by a Cardiovascular Research the Netherlands (CVON) grant of the Dutch Heart Foundation, the Dutch brain foundation and industry partners. For MR CLEAN-NO IV, the consortium received an unrestricted grant from Stryker. The study is designed and will be conducted, analyzed, and interpreted by the investigators independently of the funders and sponsor. They will not have a role in writing the report and decision to submit for publication. Publisher Copyright: © 2021, The Author(s).

PY - 2021/2/15

Y1 - 2021/2/15

N2 - Background: Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO. Methods: MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included. Discussion: IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT. Trial registration: www.isrctn.com: ISRCTN80619088. Registered on 31 October 2017.

AB - Background: Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO. Methods: MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included. Discussion: IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT. Trial registration: www.isrctn.com: ISRCTN80619088. Registered on 31 October 2017.

UR - http://www.scopus.com/inward/record.url?scp=85101451876&partnerID=8YFLogxK

U2 - 10.1186/s13063-021-05063-5

DO - 10.1186/s13063-021-05063-5

M3 - Article

SN - 1745-6215

VL - 22

JO - Trials

JF - Trials

IS - 1

M1 - 141

ER -

MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial

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