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Daniel Hanggi - One of the best experts on this subject based on the ideXlab platform.
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newton 2 cisternal Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage a phase 2 multicenter randomized open label safety study of intracisternal eg 1962 in aneurysmal subarachnoid hemorrhage
Neurosurgery, 2020Co-Authors: Loch R Macdonald, Daniel Hanggi, Stephan A Mayer, Nima Etminan, Michael N Diringer, Tim E Darsaut, Andrew P Carlson, George K C Wong, Francois E Aldrich, Poul StrangeAbstract:Background A sustained release microparticle formulation of Nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Objective To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. Methods Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg Nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. Results The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral Nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral Nimodipine patient. Four EG-1962 and the oral Nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of Nimodipine in both groups. Conclusion Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.
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clinical trial protocol phase 3 multicenter randomized double blind placebo controlled parallel group efficacy and safety study comparing eg 1962 to standard of care oral Nimodipine in adults with aneurysmal subarachnoid hemorrhage newton 2 Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Neurocritical Care, 2019Co-Authors: Daniel Hanggi, Loch R Macdonald, Stephan A Mayer, Nima Etminan, Michael N Diringer, Herbert J Faleck, Francois E Aldrich, Erich Schmutzhard, Benjamin R Saville, Newton InvestigatorsAbstract:Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of Nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release Nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral Nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2–4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral Nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral Nimodipine. The primary endpoint is the proportion of subjects with favorable outcome (6–8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.
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response by hanggi and macdonald to letter regarding article randomized open label phase 1 2a study to determine the maximum tolerated dose of intraventricular sustained release Nimodipine for subarachnoid hemorrhage newton Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Stroke, 2017Co-Authors: Daniel Hanggi, Loch R MacdonaldAbstract:We thank Professor Rustemi for his insightful comments on the NEWTON study (Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage).1 This study included standard-of-care control subjects who received enteral Nimodipine. Intravenous Nimodipine was not used because it is not available in the United States and Canada, whereas enteral Nimodipine is available in most countries worldwide. Meta-analysis of Nimodipine randomized trials reported that the efficacy of Nimodipine was based on the enteral formulation and that there was insufficient evidence to support the efficacy of intravenous Nimodipine.2 Therefore, standard-of-care control subjects in NEWTON received enteral Nimodipine.1, …
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randomized open label phase 1 2a study to determine the maximum tolerated dose of intraventricular sustained release Nimodipine for subarachnoid hemorrhage newton Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Stroke, 2017Co-Authors: Daniel Hanggi, Stephan A Mayer, Nima Etminan, Hans Jakob Steiger, Francois Aldrich, Michael N Diringer, J Mocco, Herbert J Faleck, Loch R MacdonaldAbstract:Background and Purpose— We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release Nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. Methods— Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral Nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral Nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. Results— Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral Nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral Nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P =0.027) enteral Nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral Nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). Conclusions— EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. Clinical Trial Registration— URL: . Unique identifier: [NCT01893190][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01893190&atom=%2Fstrokeaha%2F48%2F1%2F145.atom
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a site specific sustained release drug delivery system for aneurysmal subarachnoid hemorrhage
Neurotherapeutics, 2016Co-Authors: Daniel Hanggi, Nima Etminan, Hans Jakob Steiger, Mark D Johnson, Melissa M Peet, Tom Tice, Kevin Burton, Bruce W Hudson, Michele Turner, Angela R StellaAbstract:Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release Nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of Nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of Nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of Nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments.
Loch R Macdonald - One of the best experts on this subject based on the ideXlab platform.
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newton 2 cisternal Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage a phase 2 multicenter randomized open label safety study of intracisternal eg 1962 in aneurysmal subarachnoid hemorrhage
Neurosurgery, 2020Co-Authors: Loch R Macdonald, Daniel Hanggi, Stephan A Mayer, Nima Etminan, Michael N Diringer, Tim E Darsaut, Andrew P Carlson, George K C Wong, Francois E Aldrich, Poul StrangeAbstract:Background A sustained release microparticle formulation of Nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Objective To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. Methods Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg Nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. Results The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral Nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral Nimodipine patient. Four EG-1962 and the oral Nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of Nimodipine in both groups. Conclusion Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.
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clinical trial protocol phase 3 multicenter randomized double blind placebo controlled parallel group efficacy and safety study comparing eg 1962 to standard of care oral Nimodipine in adults with aneurysmal subarachnoid hemorrhage newton 2 Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Neurocritical Care, 2019Co-Authors: Daniel Hanggi, Loch R Macdonald, Stephan A Mayer, Nima Etminan, Michael N Diringer, Herbert J Faleck, Francois E Aldrich, Erich Schmutzhard, Benjamin R Saville, Newton InvestigatorsAbstract:Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of Nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release Nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral Nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2–4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral Nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral Nimodipine. The primary endpoint is the proportion of subjects with favorable outcome (6–8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.
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response by hanggi and macdonald to letter regarding article randomized open label phase 1 2a study to determine the maximum tolerated dose of intraventricular sustained release Nimodipine for subarachnoid hemorrhage newton Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Stroke, 2017Co-Authors: Daniel Hanggi, Loch R MacdonaldAbstract:We thank Professor Rustemi for his insightful comments on the NEWTON study (Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage).1 This study included standard-of-care control subjects who received enteral Nimodipine. Intravenous Nimodipine was not used because it is not available in the United States and Canada, whereas enteral Nimodipine is available in most countries worldwide. Meta-analysis of Nimodipine randomized trials reported that the efficacy of Nimodipine was based on the enteral formulation and that there was insufficient evidence to support the efficacy of intravenous Nimodipine.2 Therefore, standard-of-care control subjects in NEWTON received enteral Nimodipine.1, …
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randomized open label phase 1 2a study to determine the maximum tolerated dose of intraventricular sustained release Nimodipine for subarachnoid hemorrhage newton Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Stroke, 2017Co-Authors: Daniel Hanggi, Stephan A Mayer, Nima Etminan, Hans Jakob Steiger, Francois Aldrich, Michael N Diringer, J Mocco, Herbert J Faleck, Loch R MacdonaldAbstract:Background and Purpose— We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release Nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. Methods— Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral Nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral Nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. Results— Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral Nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral Nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P =0.027) enteral Nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral Nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). Conclusions— EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. Clinical Trial Registration— URL: . Unique identifier: [NCT01893190][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01893190&atom=%2Fstrokeaha%2F48%2F1%2F145.atom
Nima Etminan - One of the best experts on this subject based on the ideXlab platform.
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newton 2 cisternal Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage a phase 2 multicenter randomized open label safety study of intracisternal eg 1962 in aneurysmal subarachnoid hemorrhage
Neurosurgery, 2020Co-Authors: Loch R Macdonald, Daniel Hanggi, Stephan A Mayer, Nima Etminan, Michael N Diringer, Tim E Darsaut, Andrew P Carlson, George K C Wong, Francois E Aldrich, Poul StrangeAbstract:Background A sustained release microparticle formulation of Nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Objective To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. Methods Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg Nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. Results The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral Nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral Nimodipine patient. Four EG-1962 and the oral Nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of Nimodipine in both groups. Conclusion Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.
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clinical trial protocol phase 3 multicenter randomized double blind placebo controlled parallel group efficacy and safety study comparing eg 1962 to standard of care oral Nimodipine in adults with aneurysmal subarachnoid hemorrhage newton 2 Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Neurocritical Care, 2019Co-Authors: Daniel Hanggi, Loch R Macdonald, Stephan A Mayer, Nima Etminan, Michael N Diringer, Herbert J Faleck, Francois E Aldrich, Erich Schmutzhard, Benjamin R Saville, Newton InvestigatorsAbstract:Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of Nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release Nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral Nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2–4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral Nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral Nimodipine. The primary endpoint is the proportion of subjects with favorable outcome (6–8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.
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randomized open label phase 1 2a study to determine the maximum tolerated dose of intraventricular sustained release Nimodipine for subarachnoid hemorrhage newton Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Stroke, 2017Co-Authors: Daniel Hanggi, Stephan A Mayer, Nima Etminan, Hans Jakob Steiger, Francois Aldrich, Michael N Diringer, J Mocco, Herbert J Faleck, Loch R MacdonaldAbstract:Background and Purpose— We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release Nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. Methods— Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral Nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral Nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. Results— Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral Nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral Nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P =0.027) enteral Nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral Nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). Conclusions— EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. Clinical Trial Registration— URL: . Unique identifier: [NCT01893190][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01893190&atom=%2Fstrokeaha%2F48%2F1%2F145.atom
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a site specific sustained release drug delivery system for aneurysmal subarachnoid hemorrhage
Neurotherapeutics, 2016Co-Authors: Daniel Hanggi, Nima Etminan, Hans Jakob Steiger, Mark D Johnson, Melissa M Peet, Tom Tice, Kevin Burton, Bruce W Hudson, Michele Turner, Angela R StellaAbstract:Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release Nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of Nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of Nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of Nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments.
Stephan A Mayer - One of the best experts on this subject based on the ideXlab platform.
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newton 2 cisternal Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage a phase 2 multicenter randomized open label safety study of intracisternal eg 1962 in aneurysmal subarachnoid hemorrhage
Neurosurgery, 2020Co-Authors: Loch R Macdonald, Daniel Hanggi, Stephan A Mayer, Nima Etminan, Michael N Diringer, Tim E Darsaut, Andrew P Carlson, George K C Wong, Francois E Aldrich, Poul StrangeAbstract:Background A sustained release microparticle formulation of Nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Objective To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. Methods Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg Nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. Results The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral Nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral Nimodipine patient. Four EG-1962 and the oral Nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of Nimodipine in both groups. Conclusion Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.
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clinical trial protocol phase 3 multicenter randomized double blind placebo controlled parallel group efficacy and safety study comparing eg 1962 to standard of care oral Nimodipine in adults with aneurysmal subarachnoid hemorrhage newton 2 Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Neurocritical Care, 2019Co-Authors: Daniel Hanggi, Loch R Macdonald, Stephan A Mayer, Nima Etminan, Michael N Diringer, Herbert J Faleck, Francois E Aldrich, Erich Schmutzhard, Benjamin R Saville, Newton InvestigatorsAbstract:Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of Nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release Nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral Nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2–4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral Nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral Nimodipine. The primary endpoint is the proportion of subjects with favorable outcome (6–8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.
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randomized open label phase 1 2a study to determine the maximum tolerated dose of intraventricular sustained release Nimodipine for subarachnoid hemorrhage newton Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Stroke, 2017Co-Authors: Daniel Hanggi, Stephan A Mayer, Nima Etminan, Hans Jakob Steiger, Francois Aldrich, Michael N Diringer, J Mocco, Herbert J Faleck, Loch R MacdonaldAbstract:Background and Purpose— We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release Nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. Methods— Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral Nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral Nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. Results— Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral Nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral Nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P =0.027) enteral Nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral Nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). Conclusions— EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. Clinical Trial Registration— URL: . Unique identifier: [NCT01893190][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01893190&atom=%2Fstrokeaha%2F48%2F1%2F145.atom
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acute effects of Nimodipine on cerebral vasculature and brain metabolism in high grade subarachnoid hemorrhage patients
Neurocritical Care, 2012Co-Authors: Alex H Choi, Huahiou Chen, Emily J Gilmore, Amanda M Carpenter, Danielle Lee, Jan Claassen, Stephan A Mayer, Michael J Schmidt, Kiwon Lee, Sander E ConnellyAbstract:Nimodipine is the only medication shown to improve outcomes after aneurysmal subarachnoid hemorrhage (SAH). Preliminary theories regarding the mechanism by which it prevents vasospasm have been challenged. The acute physiologic and metabolic effects of oral Nimodipine have not been examined in patients with poor-grade SAH. This is an observational study performed in 16 poor-grade SAH patients undergoing multimodality monitoring who received oral Nimodipine as part of routine clinical care. A total of 663 doses of Nimodipine were observed. Changes in physiologic measurements including MAP, CPP, ICP, PbtO2, and CBF were examined. Administration of oral Nimodipine was associated with a 1.33 mmHg decrease in MAP (P < 0.001) and a 1.22 mmHg decrease in CPP (P < 0.001). When administration of Nimodipine was associated with MAP decreases, PbtO2 (1.03 mmHg; P < 0.001) and CBF (0.39 ml/100 g/min; P = 0.002) also decreased. Despite CPP targeted therapy with vasopressor medication, oral Nimodipine was associated with a decrease in MAP and CPP. When Nimodipine administration was associated with a decrease in MAP, there were concomitant drops in PbtO2 and CBF. These findings suggest that MAP support after oral Nimodipine may be important to maintain adequate CBF in patients with poor-grade subarachnoid hemorrhage.
Michael N Diringer - One of the best experts on this subject based on the ideXlab platform.
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newton 2 cisternal Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage a phase 2 multicenter randomized open label safety study of intracisternal eg 1962 in aneurysmal subarachnoid hemorrhage
Neurosurgery, 2020Co-Authors: Loch R Macdonald, Daniel Hanggi, Stephan A Mayer, Nima Etminan, Michael N Diringer, Tim E Darsaut, Andrew P Carlson, George K C Wong, Francois E Aldrich, Poul StrangeAbstract:Background A sustained release microparticle formulation of Nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Objective To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. Methods Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg Nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. Results The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral Nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral Nimodipine patient. Four EG-1962 and the oral Nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of Nimodipine in both groups. Conclusion Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.
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clinical trial protocol phase 3 multicenter randomized double blind placebo controlled parallel group efficacy and safety study comparing eg 1962 to standard of care oral Nimodipine in adults with aneurysmal subarachnoid hemorrhage newton 2 Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Neurocritical Care, 2019Co-Authors: Daniel Hanggi, Loch R Macdonald, Stephan A Mayer, Nima Etminan, Michael N Diringer, Herbert J Faleck, Francois E Aldrich, Erich Schmutzhard, Benjamin R Saville, Newton InvestigatorsAbstract:Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of Nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release Nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral Nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2–4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral Nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral Nimodipine. The primary endpoint is the proportion of subjects with favorable outcome (6–8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.
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randomized open label phase 1 2a study to determine the maximum tolerated dose of intraventricular sustained release Nimodipine for subarachnoid hemorrhage newton Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage
Stroke, 2017Co-Authors: Daniel Hanggi, Stephan A Mayer, Nima Etminan, Hans Jakob Steiger, Francois Aldrich, Michael N Diringer, J Mocco, Herbert J Faleck, Loch R MacdonaldAbstract:Background and Purpose— We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release Nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. Methods— Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral Nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral Nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. Results— Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral Nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral Nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P =0.027) enteral Nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral Nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). Conclusions— EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. Clinical Trial Registration— URL: . Unique identifier: [NCT01893190][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01893190&atom=%2Fstrokeaha%2F48%2F1%2F145.atom