Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage

Andrew P. Carlson; Daniel Hänggi; George K. Wong; Nima Etminan; Stephan A. Mayer; François Aldrich; Michael N. Diringer; Erich Schmutzhard; Herbert J. Faleck; David Ng; Benjamin R. Saville; Thomas Bleck; Robert Grubb; Michael Miller; Jose I. Suarez; Howard M. Proskin; R. Loch MacDonald; Amal Abou-Hamden; Rodney Allan; Laith Altaweel; Arun Amar; Sepideh Amin-Hanjani; Khaled Aziz; Nicholas Bambakidis; Michel Bojanowski; Ondrej Bradac; Sherry Chou; Wayne Marston Clark; Tim Darsaut; Koji C. Ebersole; Lucas Elijovich; William D. Freeman; Roland Goldbrunner; Carmelo Graffagnino; Gaurav Gupta; Jirina Habalova; Moshe Hadani; Sagi Harnof; Mark Robert Harrigan; Kevin Hatton; Raimund Helbok; Tomas Hrbac; Hagen B. Huttner; Pascal Jabbour; Babak Jahromi; Robert James; Joseph Dedrick Jordan; Michael Kelly; Riku P. Kivisaari; Nerissa Ko; Jürgen Konczalla; David Kung; Shouri Lahiri; David Langer; Matthew Lawson; Cappi Lay; David Ledoux; George A. Lopez; Wai Man Lui; Charles Matouk; Edward W. Mee; Jürgen Meixensberger; Oliver Müller; Vincent Ng Yew Poh; Juha Öhman; Peter Papadakos; Aman B. Patel; Adam Polifka; Wai Sang Poon; Ciaran Powers; John Reavey-Cantwell; Gary Redekop; Jan Regelsberger; Guy Rosenthal; Yu Mi Ryang; Eric Sauvageau; Ian Seppelt; Martin Smrcka; Julian Spears; Ajith Thomas; Raymond Turner; Andreas Unterberg; Peter Vajkoczy; Paul Vespa; Daniel E. Walzman; Thomas Westermaier; John Wong; Menashe Zaaroor; Joseph Zabramski

doi:10.1161/STROKEAHA.119.027396

Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage

Andrew P. Carlson, Daniel Hänggi, George K. Wong, Nima Etminan, Stephan A. Mayer, François Aldrich, Michael N. Diringer, Erich Schmutzhard, Herbert J. Faleck, David Ng, Benjamin R. Saville, Thomas Bleck, Robert Grubb, Michael Miller, Jose I. Suarez, Howard M. Proskin, R. Loch MacDonald, Amal Abou-Hamden, Rodney Allan, Laith AltaweelArun Amar, Sepideh Amin-Hanjani, Khaled Aziz, Nicholas Bambakidis, Michel Bojanowski, Ondrej Bradac, Sherry Chou, Wayne Marston Clark, Tim Darsaut, Koji C. Ebersole, Lucas Elijovich, William D. Freeman, Roland Goldbrunner, Carmelo Graffagnino, Gaurav Gupta, Jirina Habalova, Moshe Hadani, Sagi Harnof, Mark Robert Harrigan, Kevin Hatton, Raimund Helbok, Tomas Hrbac, Hagen B. Huttner, Pascal Jabbour, Babak Jahromi, Robert James, Joseph Dedrick Jordan, Michael Kelly, Riku P. Kivisaari, Nerissa Ko, Jürgen Konczalla, David Kung, Shouri Lahiri, David Langer, Matthew Lawson, Cappi Lay, David Ledoux, George A. Lopez, Wai Man Lui, Charles Matouk, Edward W. Mee, Jürgen Meixensberger, Oliver Müller, Vincent Ng Yew Poh, Juha Öhman, Peter Papadakos, Aman B. Patel, Adam Polifka, Wai Sang Poon, Ciaran Powers, John Reavey-Cantwell, Gary Redekop, Jan Regelsberger, Guy Rosenthal, Yu Mi Ryang, Eric Sauvageau, Ian Seppelt, Martin Smrcka, Julian Spears, Ajith Thomas, Raymond Turner, Andreas Unterberg, Peter Vajkoczy, Paul Vespa, Daniel E. Walzman, Thomas Westermaier, John Wong, Menashe Zaaroor, Joseph Zabramski

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

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Abstract

Background and Purpose - EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods - Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results - The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions - There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable.

Original language	English
Pages (from-to)	1142-1149
Number of pages	8
Journal	Stroke
Volume	51
Issue number	4
DOIs	https://doi.org/10.1161/STROKEAHA.119.027396
State	Published - Apr 1 2020

Keywords

clinical trial
infarction
nimodipine
standard of care
subarachnoid hemorrhage

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10.1161/STROKEAHA.119.027396

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Carlson, A. P., Hänggi, D., Wong, G. K., Etminan, N., Mayer, S. A., Aldrich, F., Diringer, M. N., Schmutzhard, E., Faleck, H. J., Ng, D., Saville, B. R., Bleck, T., Grubb, R., Miller, M., Suarez, J. I., Proskin, H. M., MacDonald, R. L., Abou-Hamden, A., Allan, R., ... Zabramski, J. (2020). Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage. Stroke, 51(4), 1142-1149. https://doi.org/10.1161/STROKEAHA.119.027396

@article{4ed3ec4dbfcd4c33b020536b30d92a9a,

title = "Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage",

abstract = "Background and Purpose - EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods - Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results - The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions - There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable.",

keywords = "clinical trial, infarction, nimodipine, standard of care, subarachnoid hemorrhage",

author = "Carlson, {Andrew P.} and Daniel H{\"a}nggi and Wong, {George K.} and Nima Etminan and Mayer, {Stephan A.} and Fran{\c c}ois Aldrich and Diringer, {Michael N.} and Erich Schmutzhard and Faleck, {Herbert J.} and David Ng and Saville, {Benjamin R.} and Thomas Bleck and Robert Grubb and Michael Miller and Suarez, {Jose I.} and Proskin, {Howard M.} and MacDonald, {R. Loch} and Amal Abou-Hamden and Rodney Allan and Laith Altaweel and Arun Amar and Sepideh Amin-Hanjani and Khaled Aziz and Nicholas Bambakidis and Michel Bojanowski and Ondrej Bradac and Sherry Chou and Clark, {Wayne Marston} and Tim Darsaut and Ebersole, {Koji C.} and Lucas Elijovich and Freeman, {William D.} and Roland Goldbrunner and Carmelo Graffagnino and Gaurav Gupta and Jirina Habalova and Moshe Hadani and Sagi Harnof and Harrigan, {Mark Robert} and Kevin Hatton and Raimund Helbok and Tomas Hrbac and Huttner, {Hagen B.} and Pascal Jabbour and Babak Jahromi and Robert James and Jordan, {Joseph Dedrick} and Michael Kelly and Kivisaari, {Riku P.} and Nerissa Ko and J{\"u}rgen Konczalla and David Kung and Shouri Lahiri and David Langer and Matthew Lawson and Cappi Lay and David Ledoux and Lopez, {George A.} and Lui, {Wai Man} and Charles Matouk and Mee, {Edward W.} and J{\"u}rgen Meixensberger and Oliver M{\"u}ller and {Ng Yew Poh}, Vincent and Juha {\"O}hman and Peter Papadakos and Patel, {Aman B.} and Adam Polifka and Poon, {Wai Sang} and Ciaran Powers and John Reavey-Cantwell and Gary Redekop and Jan Regelsberger and Guy Rosenthal and Ryang, {Yu Mi} and Eric Sauvageau and Ian Seppelt and Martin Smrcka and Julian Spears and Ajith Thomas and Raymond Turner and Andreas Unterberg and Peter Vajkoczy and Paul Vespa and Walzman, {Daniel E.} and Thomas Westermaier and John Wong and Menashe Zaaroor and Joseph Zabramski",

note = "Funding Information: The study was funded by Edge Therapeutics. Publisher Copyright: {\textcopyright} 2020 American Heart Association, Inc.",

year = "2020",

month = apr,

day = "1",

doi = "10.1161/STROKEAHA.119.027396",

language = "English",

volume = "51",

pages = "1142--1149",

journal = "Stroke",

issn = "0039-2499",

number = "4",

}

Carlson, AP, Hänggi, D, Wong, GK, Etminan, N, Mayer, SA, Aldrich, F, Diringer, MN, Schmutzhard, E, Faleck, HJ, Ng, D, Saville, BR, Bleck, T, Grubb, R, Miller, M, Suarez, JI, Proskin, HM, MacDonald, RL, Abou-Hamden, A, Allan, R, Altaweel, L, Amar, A, Amin-Hanjani, S, Aziz, K, Bambakidis, N, Bojanowski, M, Bradac, O, Chou, S, Clark, WM, Darsaut, T, Ebersole, KC, Elijovich, L, Freeman, WD, Goldbrunner, R, Graffagnino, C, Gupta, G, Habalova, J, Hadani, M, Harnof, S, Harrigan, MR, Hatton, K, Helbok, R, Hrbac, T, Huttner, HB, Jabbour, P, Jahromi, B, James, R, Jordan, JD, Kelly, M, Kivisaari, RP, Ko, N, Konczalla, J, Kung, D, Lahiri, S, Langer, D, Lawson, M, Lay, C, Ledoux, D, Lopez, GA, Lui, WM, Matouk, C, Mee, EW, Meixensberger, J, Müller, O, Ng Yew Poh, V, Öhman, J, Papadakos, P, Patel, AB, Polifka, A, Poon, WS, Powers, C, Reavey-Cantwell, J, Redekop, G, Regelsberger, J, Rosenthal, G, Ryang, YM, Sauvageau, E, Seppelt, I, Smrcka, M, Spears, J, Thomas, A, Turner, R, Unterberg, A, Vajkoczy, P, Vespa, P, Walzman, DE, Westermaier, T, Wong, J, Zaaroor, M & Zabramski, J 2020, 'Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage', Stroke, vol. 51, no. 4, pp. 1142-1149. https://doi.org/10.1161/STROKEAHA.119.027396

TY - JOUR

T1 - Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage

AU - Carlson, Andrew P.

AU - Hänggi, Daniel

AU - Wong, George K.

AU - Etminan, Nima

AU - Mayer, Stephan A.

AU - Aldrich, François

AU - Diringer, Michael N.

AU - Schmutzhard, Erich

AU - Faleck, Herbert J.

AU - Ng, David

AU - Saville, Benjamin R.

AU - Bleck, Thomas

AU - Grubb, Robert

AU - Miller, Michael

AU - Suarez, Jose I.

AU - Proskin, Howard M.

AU - MacDonald, R. Loch

AU - Abou-Hamden, Amal

AU - Allan, Rodney

AU - Altaweel, Laith

AU - Amar, Arun

AU - Amin-Hanjani, Sepideh

AU - Aziz, Khaled

AU - Bambakidis, Nicholas

AU - Bojanowski, Michel

AU - Bradac, Ondrej

AU - Chou, Sherry

AU - Clark, Wayne Marston

AU - Darsaut, Tim

AU - Ebersole, Koji C.

AU - Elijovich, Lucas

AU - Freeman, William D.

AU - Goldbrunner, Roland

AU - Graffagnino, Carmelo

AU - Gupta, Gaurav

AU - Habalova, Jirina

AU - Hadani, Moshe

AU - Harnof, Sagi

AU - Harrigan, Mark Robert

AU - Hatton, Kevin

AU - Helbok, Raimund

AU - Hrbac, Tomas

AU - Huttner, Hagen B.

AU - Jabbour, Pascal

AU - Jahromi, Babak

AU - James, Robert

AU - Jordan, Joseph Dedrick

AU - Kelly, Michael

AU - Kivisaari, Riku P.

AU - Ko, Nerissa

AU - Konczalla, Jürgen

AU - Kung, David

AU - Lahiri, Shouri

AU - Langer, David

AU - Lawson, Matthew

AU - Lay, Cappi

AU - Ledoux, David

AU - Lopez, George A.

AU - Lui, Wai Man

AU - Matouk, Charles

AU - Mee, Edward W.

AU - Meixensberger, Jürgen

AU - Müller, Oliver

AU - Ng Yew Poh, Vincent

AU - Öhman, Juha

AU - Papadakos, Peter

AU - Patel, Aman B.

AU - Polifka, Adam

AU - Poon, Wai Sang

AU - Powers, Ciaran

AU - Reavey-Cantwell, John

AU - Redekop, Gary

AU - Regelsberger, Jan

AU - Rosenthal, Guy

AU - Ryang, Yu Mi

AU - Sauvageau, Eric

AU - Seppelt, Ian

AU - Smrcka, Martin

AU - Spears, Julian

AU - Thomas, Ajith

AU - Turner, Raymond

AU - Unterberg, Andreas

AU - Vajkoczy, Peter

AU - Vespa, Paul

AU - Walzman, Daniel E.

AU - Westermaier, Thomas

AU - Wong, John

AU - Zaaroor, Menashe

AU - Zabramski, Joseph

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Background and Purpose - EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods - Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results - The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions - There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable.

AB - Background and Purpose - EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods - Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results - The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions - There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable.

KW - clinical trial

KW - infarction

KW - nimodipine

KW - standard of care

KW - subarachnoid hemorrhage

UR - http://www.scopus.com/inward/record.url?scp=85082342024&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.119.027396

DO - 10.1161/STROKEAHA.119.027396

M3 - Article

C2 - 32138631

AN - SCOPUS:85082342024

SN - 0039-2499

VL - 51

SP - 1142

EP - 1149

JO - Stroke

JF - Stroke

IS - 4

ER -

Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage

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