Evidence map›Paper›PMID 27932607›Full record

Trial reportStroke2017

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]).

Daniel Hänggi, Nima Etminan, Francois Aldrich, Hans Jakob Steiger, Stephan A Mayer, Michael N Diringer, Brian L Hoh, J Mocco, Herbert J Faleck, R Loch Macdonald and 1 more

Registry-linked trialOpen access · hybridAbstract readClinical Trial, Phase IClinical Trial, Phase IIMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Stroke, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01893190 (Nimodipine Microparticles to Enhance Recovery While Reducing TOxicity After subarachNoid Hemorrhage), which is not on this map. Cited by 32 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed, 3 pooled it
6.7field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01893190 phase1 / phase2completednot on this map

Nimodipine Microparticles to Enhance Recovery While Reducing TOxicity After subarachNoid Hemorrhage: Phase I/IIa Multicenter, Controlled, Randomized, Open Label, Dose Escalation, Safety, Tolerability, and Pharmacokinectic Study Comparing EG-1962 and Nimodipine in Patients With Aneurysmal Subarachnoid Hemorrhage

TypeinterventionalSponsorEdge Therapeutics IncRan2013 to 2016Enrolled73ConditionsRuptured Cerebral Aneurysm, Ruptured Berry AneurysmArmsNimodipine, Nimodipine Microparticles
3 · Its place in the literature

Who cites it

32 citing papers in PubMed, 3 syntheses or guidelines pooled it, 74 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Intrathecal drug delivery in the era of nanomedicine.Advanced drug delivery reviews · 2020
    Pooled it
  4. Trial
  5. Article
  6. Article
  7. Review
  8. Article
  9. Article
  10. Observational
  11. Review
  12. Outcomes Measures in Subarachnoid Hemorrhage Research.Translational stroke research · 2025
    Review
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  14. Review
  15. Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors at 6 institutions in 3 countries.

Daniel HänggiFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.). daniel.haenggi@medma.uni-heidelberg.de.
Nima EtminanFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
Francois AldrichFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
Hans Jakob SteigerFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
Stephan A MayerFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
Michael N DiringerFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
Brian L HohFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
J MoccoFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
Herbert J FaleckFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
R Loch MacdonaldFrom the Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany (D.H., N.E.); Neurological Surgery, University of Maryland Medical Center, Baltimore (F.A.); Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany (H.J.S.); Institute for Critical Care Medicine and Department of Neurosurgery, Mount Sinai Hospital, New York (S.A.M., J.M.); Neurological Critical Care, Washington University School of Medicine, St. Louis, MO (M.N.D.); Department of Neurosurgery, University of Florida, Gainesville (B.L.H.); Division of Neurosurgery, St. Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery, University of Toronto, Canada (R.L.M.); and Edge Therapeutics, Berkeley Heights, NJ (R.L.M., H.J.F.).
NEWTON Investigators
University of Maryland, Baltimore · USNeurological Surgery · USWashington University in St. Louis · USSt. Michael's Hospital · CAUniversity Hospital Heidelberg · DEUniversity of Maryland Medical Center · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

background and purposeWe 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.

methodsSubjects 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.

resultsFifty-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%]).

conclusionsEG-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 registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190.

Indexed as

Maximum Tolerated DoseMicrospheresAdultAgedCalcium Channel BlockersCohort StudiesDelayed-Action PreparationsFemaleHumansInjections, IntraventricularMaleMiddle AgedNimodipineRecovery of FunctionSubarachnoid HemorrhageCalcium Channel BlockersDelayed-Action PreparationsNimodipinebrain ischemiahypotensionnimodipinesubarachnoid hemorrhagesustained release formulation

Identifiers

PMID27932607
PMCPMC5176000
OpenAlexW2560508979

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LicenceCC BY-NC-ND
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.