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)]
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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.
KeywordsCerebral aneurysm Clinical trial Delayed cerebral ischemia Extended release Nimodipine Subarachnoid hemorrhage aSAH
The protocol was designed by DH, NE, SAM, FA, MND, ES, HJF, RLM, DN, and BRS.
Source of support
Edge herapeutics, Inc. is funding the study. Funding is provided not to the investigators themselves but to the sites for study-related costs.
Compliance with Ethical Standards
Conflict of interest
RL. Macdonald receives grant support from the Brain Aneurysm Foundation and the Canadian Institutes for Health Research and is Chief Scientific Officer of Edge Therapeutics, Inc. D. Hänggi, N. Etminan, F. Aldrich, S.A. Mayer, M.N. Diringer, and E. Schmutzhard receive consulting fees from Edge Therapeutics, Inc. for serving on the steering committee for this study and for advising Edge Therapeutics, Inc. H.J. Faleck is an employee of Edge Therapeutics, Inc. D. Ng is an employee of ResearchPoint Global. B.R. Saville is an employee of Berry Consultants.
- 1.Chan AW, Tetzlaff JM, Gotzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.Google Scholar
- 2.Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007;3:CD000277.Google Scholar
- 3.Nieuwkamp DJ, Setz LE, Algra A, et al. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009;8(7):635–42.Google Scholar
- 4.Sandow N, Diesing D, Sarrafzadeh A, Vajkoczy P, Wolf S. Nimodipine dose reductions in the treatment of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2016;25(1):29–39.Google Scholar
- 5.Abboud T, Andresen H, Koeppen J, et al. Serum levels of nimodipine in enteral and parenteral administration in patients with aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 2015;157(5):763–7.Google Scholar
- 6.Hanggi D, Etminan N, Steiger HJ, et al. A site-specific, sustained-release drug delivery system for aneurysmal Subarachnoid hemorrhage. Neurotherapeutics. 2016;13(2):439–49.Google Scholar
- 7.Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm–a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 1983;308(11):619–24.Google Scholar
- 8.Porchet F, Chiolero R, de Tribolet N. Hypotensive effect of nimodipine during treatment for aneurysmal subarachnoid haemorrhage. Acta Neurochir. 1995;137(1–2):62–9.Google Scholar
- 9.Petruk KC, West M, Mohr G, et al. Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial. J Neurosurg. 1988;68(4):505–17.Google Scholar
- 10.Burrows AM, Korumilli R, Lanzino G. How we do it: acute management of subarachnoid hemorrhage. Neurol Res. 2013;35(2):111–6.Google Scholar
- 11.Stevens RD, Naval NS, Mirski MA, Citerio G, Andrews PJ. Intensive care of aneurysmal subarachnoid hemorrhage: an international survey. Intensive Care Med. 2009;35(9):1556–66.Google Scholar
- 12.Rabinstein AA, Lanzino G, Wijdicks EF. Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol. 2010;9(5):504–19.Google Scholar
- 13.Diringer MN, Bleck TP, Hemphill CJ III, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15(2):211–40.Google Scholar
- 14.Barth M, Capelle HH, Weidauer S, et al. Effect of nicardipine prolonged-release implants on cerebral vasospasm and clinical outcome after severe aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind phase IIa study. Stroke. 2007;38(2):330–6.Google Scholar
- 15.Kasuya H, Onda H, Sasahara A, Takeshita M, Hori T. Application of nicardipine prolonged-release implants: analysis of 97 consecutive patients with acute subarachnoid hemorrhage. Neurosurgery. 2005;56(5):895–902.Google Scholar
- 16.Lu N, Jackson D, Luke S, et al. Intraventricular nicardipine for aneurysmal subarachnoid hemorrhage related vasospasm: assessment of 90 days outcome. Neurocrit Care. 2012;16(3):368–75.Google Scholar
- 17.Dabus G, Nogueira RG. Current options for the management of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: a comprehensive review of the literature. Interv Neurol. 2013;2(1):30–51.Google Scholar
- 18.Abruzzo T, Moran C, Blackham KA, et al. Invasive interventional management of post-hemorrhagic cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurointerv Surg. 2012;4(3):169–77.Google Scholar
- 19.Hanggi D, Beseoglu K, Turowski B, Steiger HJ. Feasibility and safety of intrathecal nimodipine on posthaemorrhagic cerebral vasospasm refractory to medical and endovascular therapy. Clin Neurol Neurosurg. 2008;110(8):784–90.Google Scholar
- 20.Rosenberg N, Lazzaro MA, Lopes DK, Prabhakaran S. High-dose intra-arterial nicardipine results in hypotension following vasospasm treatment in subarachnoid hemorrhage. Neurocrit Care. 2011;15(3):400–4.Google Scholar
- 21.Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10(1):44–58.Google Scholar
- 22.Dreier JP, Major S, Manning A, et al. Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain. 2009;132(Pt 7):1866–81.Google Scholar
- 23.Pisapia JM, Xu X, Kelly J, et al. Microthrombosis after experimental subarachnoid hemorrhage: time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan. Exp Neurol. 2012;233(1):357–63.Google Scholar
- 24.Budohoski KP, Czosnyka M, Smielewski P, et al. Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: a prospective observational study. Stroke. 2012;43(12):3230–7.Google Scholar
- 25.Ostergaard L, Aamand R, Karabegovic S, et al. The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2013;33(12):1825–37.Google Scholar
- 26.Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389(10069):655–66.Google Scholar
- 27.Sehba FA, Hou J, Pluta RM, Zhang JH. The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol. 2012;97(1):14–37.Google Scholar
- 28.Etminan N, Macdonald RL, Davis C, et al. Intrathecal application of the nimodipine slow-release microparticle system eg-1962 for prevention of delayed cerebral ischemia and improvement of outcome after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl. 2015;120:281–6.Google Scholar
- 29.Hanggi D, Etminan N, Macdonald RL, et al. NEWTON: Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachNoid hemorrhage. Neurocrit Care. 2015;23(2):274–84.Google Scholar
- 30.Hanggi D, Etminan N, Aldrich F, et al. 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. 2017;48(1):145–51.Google Scholar
- 31.Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9.Google Scholar
- 32.McMillan T, Wilson L, Ponsford J, et al. The glasgow outcome scale—40 years of application and refinement. Nat Rev Neurol. 2016;12(8):477–85.Google Scholar
- 33.Vergouwen MD, Vermeulen M, van Gijn J, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010;41(10):2391–5.Google Scholar
- 34.van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn G. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604–7.Google Scholar
- 35.Teasdale G, Maas A, Lecky F, et al. The glasgow coma scale at 40 years: standing the test of time. Lancet Neurol. 2014;13(8):844–54.Google Scholar
- 36.Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012;43(6):1711–37.Google Scholar
- 37.Chung DY, Leslie-Mazwi TM, Patel AB, Rordorf GA. Management of external ventricular drains after subarachnoid hemorrhage: a multi-institutional survey. Neurocrit Care. 2017;26(3):356–61.Google Scholar
- 38.Degen LA, Dorhout Mees SM, Algra A, Rinkel GJ. Interobserver variability of grading scales for aneurysmal subarachnoid hemorrhage. Stroke. 2011;42(6):1546–9.Google Scholar
- 39.Drake CG, Hunt WE, Sano K, et al. Report of World Federation of Neurological Surgeons committee on a universal subarachnoid hemorrhage grading scale. J Neurosurg. 1988;68:985–6.Google Scholar
- 40.Frontera JA, Claassen J, Schmidt JM, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59(1):21–7.Google Scholar
- 41.Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the glasgow outcome scale and the extended glasgow outcome scale: guidelines for their use. J Neurotrauma. 1998;15(8):573–85.Google Scholar
- 42.Wilby MJ, Sharp M, Whitfield PC, et al. Cost-effective outcome for treating poor-grade subarachnoid hemorrhage. Stroke. 2003;34(10):2508–11.Google Scholar
- 43.Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet. 2002;359(9307):696–700.Google Scholar