Response by Hänggi 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])”
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.1,3
We support the theory that the earlier after aneurysmal subarachnoid hemorrhage that one can start administering nimodipine, the better.
We agree that NEWTON included a limited number of subjects. It was designed as a phase 1/2 dose-finding, safety, tolerability, and pharmacokinetic study with clinical outcomes as exploratory end points. We were not anticipating significant effects on exploratory end points, but we were intrigued by the observed reductions in angiographic vasospasm, delayed cerebral ischemia, use of rescue therapy, and the increase in favorable outcome with intraventricular sustained-release nimodipine (EG-1962). The results of NEWTON supported initiation of the ongoing NEWTON-2 pivotal phase 3 clinical study, which compares the efficacy and safety of intraventricular EG-1962 with oral nimodipine. In addition, a study to determine safety, pharmacokinetics, and clinical end points of intracisternal administration of EG-1962 also is underway. Although ventriculitis/meningitis are obviously of concern and to be avoided, adherence to guidelines for insertion and care of external ventricular drains can reduce the risk of infection.4 Fortunately, many of these infections resolve with treatment. In NEWTON, there were 5 cases of culture-positive ventriculitis/meningitis in subjects treated with EG-1962. All infections were associated with prolonged ventricular drainage, a known risk factor for external ventricular drain infection. The clinical outcome, which at the end of the day is what matters most, was favorable in 4 of 5 subjects (80%) with positive cultures.
Daniel Hänggi, MD
Department of Neurosurgery
University Hospital Mannheim, Medical Faculty Mannheim
University of Heidelberg
R. Loch Macdonald, MD, PhD
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
Dr Macdonald receives grant support from the Physicians Services Incorporated Foundation, Brain Aneurysm Foundation, Canadian Institutes for Health Research, and the Heart and Stroke Foundation of Canada and is an employee and Chief Scientific Officer of Edge Therapeutics, Inc. Dr Hänggi receives consulting fees from Edge Therapeutics, Inc. for serving on the steering committee for this trial and for advising Edge Therapeutics, Inc.
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