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NEWTON: Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage

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Abstract

Background

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. EG-1962 is a sustained-release microparticle formulation of nimodipine that has shown preclinical efficacy when administered intraventricularly or intracisternally to dogs with SAH, without evidence of toxicity at doses in the anticipated therapeutic range. Thus, we propose to administer EG-1962 to humans in order to assess safety and tolerability and determine a dose to investigate efficacy in subsequent clinical studies.

Methods

We describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of EG-1962 in patients with aSAH. The study will comprise two parts: a dose escalation period (Part 1) to determine the MTD of EG-1962 and a treatment period (Part 2) to assess the safety and tolerability of the selected dose of EG-1962. Patients with a ruptured saccular aneurysm treated by neurosurgical clipping or endovascular coiling will be considered for enrollment. Patients will be randomized to receive either EG-1962 (study drug: nimodipine microparticles) or oral nimodipine in the approved dose regimen (active control) within 60 h of aSAH.

Results

Primary objectives are to determine the MTD and the safety and tolerability of the selected dose of intraventricular EG-1962 as compared to enteral nimodipine. The secondary objective is to determine release and distribution by measuring plasma and CSF concentrations of nimodipine. Exploratory objectives are to determine the incidence of delayed cerebral infarction on computed tomography, clinical features of delayed cerebral ischemia, angiographic vasospasm, and incidence of rescue therapy and clinical outcome. Clinical outcome will be determined at 90 days after aSAH using the extended Glasgow outcome scale, modified Rankin scale, Montreal cognitive assessment, telephone interview of cognitive status, and Barthel index.

Conclusion

Here, we describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the MTD and assess the safety and tolerability of EG-1962 in patients with aSAH.

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References

  1. Chan AW, Tetzlaff JM, Gotzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Liu X, Rinkel GJ. Aneurysmal and clinical characteristics as risk factors for intracerebral haematoma from aneurysmal rupture. J Neurol. 2011;258(5):862–5.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007;3:CD000277.

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Dankbaar JW, Slooter AJ, Rinkel GJ, van der Schaaf IC. Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review. Crit Care. 2010;14(1):R23.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Darby JM, Yonas H, Marks EC, Durham S, Snyder RW, Nemoto EM. Acute cerebral blood flow response to dopamine-induced hypertension after subarachnoid hemorrhage. J Neurosurg. 1994;80(5):857–64.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    PubMed  Google Scholar 

  11. Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10(1):44–58.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  Google Scholar 

  15. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Vinge E, Andersson KE, Brandt L, Ljunggren B, Nilsson LG, Rosendal-Helgesen S. Pharmacokinetics of nimodipine in patients with aneurysmal subarachnoid haemorrhage. Eur J Clin Pharmacol. 1986;30(4):421–5.

    Article  CAS  PubMed  Google Scholar 

  17. Cook DJ, Kan S, Ai J, Kasuya H, Macdonald RL. Cisternal sustained release dihydropyridines for subarachnoid hemorrhage. Curr Neurovasc Res. 2012;9(2):139–48.

    Article  CAS  PubMed  Google Scholar 

  18. Dreier JP, Windmuller O, Petzold G, Lindauer U, Einhaupl KM, Dirnagl U. Ischemia triggered by red blood cell products in the subarachnoid space is inhibited by nimodipine administration or moderate volume expansion/hemodilution in rats. Neurosurgery. 2002;51(6):1457–65.

    PubMed  Google Scholar 

  19. Vergouwen MD, Vermeulen M, de Haan RJ, Levi M, Roos YB. Dihydropyridine calcium antagonists increase fibrinolytic activity: a systematic review. J Cereb Blood Flow Metab. 2007;27(7):1293–308.

    Article  CAS  PubMed  Google Scholar 

  20. Radhakrishnan D, Menon DK. Haemodynamic effects of intravenous nimodipine following aneurysmal subarachnoid haemorrhage: implications for monitoring. Anaesthesia. 1997;52(5):489–91.

    Article  CAS  PubMed  Google Scholar 

  21. Kasuya H, Onda H, Takeshita M, Okada Y, Hori T. Efficacy and safety of nicardipine prolonged-release implants for preventing vasospasm in humans. Stroke. 2002;33(4):1011–5.

    Article  CAS  PubMed  Google Scholar 

  22. Kasuya H. Clinical trial of nicardipine prolonged-release implants for preventing cerebral vasospasm: multicenter cooperative study in Tokyo. Acta Neurochir Suppl. 2011;110(2):165–7.

    CAS  PubMed  Google Scholar 

  23. Krischek B, Kasuya H, Onda H, Hori T. Nicardipine prolonged-release implants for preventing cerebral vasospasm after subarachnoid hemorrhage: effect and outcome in the first 100 patients. Neurol Med Chir. 2007;47(9):389–94.

    Article  Google Scholar 

  24. Barth M, Pena P, Seiz M, et al. Feasibility of intraventricular nicardipine prolonged release implants in patients following aneurysmal subarachnoid haemorrhage. Br J Neurosurg. 2011;25(6):677–83.

    Article  PubMed  Google Scholar 

  25. Ehtisham A, Taylor S, Bayless L, Samuels OB, Klein MW, Janzen JM. Use of intrathecal nicardipine for aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm. South Med J. 2009;102(2):150–3.

    Article  PubMed  Google Scholar 

  26. Goodson K, Lapointe M, Monroe T, Chalela JA. Intraventricular nicardipine for refractory cerebral vasospasm after subarachnoid hemorrhage. Neurocrit Care. 2008;8(2):247–52.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  PubMed  Google Scholar 

  28. Lu N, Jackson D, Luke S, Festic E, Hanel RA, Freeman WD. Intraventricular nicardipine for aneurysmal subarachnoid hemorrhage related vasospasm: assessment of 90 days outcome. Neurocrit Care. 2012;16(3):368–75.

    Article  CAS  PubMed  Google Scholar 

  29. Shibuya M, Suzuki Y, Enomoto H, Okada T, Ogura K, Sugita K. Effects of prophylactic intrathecal administrations of nicardipine on vasospasm in patients with severe aneurysmal subarachnoid haemorrhage. Acta Neurochir. 1994;131(1–2):19–25.

    Article  CAS  PubMed  Google Scholar 

  30. Biondi A, Ricciardi GK, Puybasset L, et al. Intra-arterial nimodipine for the treatment of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage: preliminary results. Am J Neuroradiol. 2004;25(6):1067–76.

    PubMed  Google Scholar 

  31. Cho WS, Kang HS, Kim JE, et al. Intra-arterial nimodipine infusion for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. Interv Neuroradiol. 2011;17(2):169–78.

    PubMed Central  PubMed  Google Scholar 

  32. Kim SS, Park DH, Lim DJ, Kang SH, Cho TH, Chung YG. Angiographic features and clinical outcomes of intra-arterial nimodipine injection in patients with subarachnoid hemorrhage-induced vasospasm. J Korean Neurosurg Soc. 2012;52(3):172–8.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Musahl C, Henkes H, Vajda Z, Coburger J, Hopf N. Continuous local intra-arterial nimodipine administration in severe symptomatic vasospasm after subarachnoid hemorrhage. Neurosurgery. 2011;68(6):1541–7.

    Article  PubMed  Google Scholar 

  34. Wolf S, Martin H, Landscheidt JF, Rodiek SO, Schurer L, Lumenta CB. Continuous selective intraarterial infusion of nimodipine for therapy of refractory cerebral vasospasm. Neurocrit Care. 2010;12(3):346–51.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  PubMed  Google Scholar 

  36. Menei P, Montero-Menei C, Venier MC, Benoit JP. Drug delivery into the brain using poly(lactide-co-glycolide) microspheres. Expert Opin Drug Deliv. 2005;2(2):363–76.

    Article  CAS  PubMed  Google Scholar 

  37. Lemperle G, Morhenn VB, Pestonjamasp V, Gallo RL. Migration studies and histology of injectable microspheres of different sizes in mice. Plast Reconstr Surg. 2004;113(5):1380–90.

    Article  PubMed  Google Scholar 

  38. Nicholas AP, McInnis C, Gupta KB, et al. The fate of biodegradable microspheres injected into rat brain. Neurosci Lett. 2002;323(2):85–8.

    Article  CAS  PubMed  Google Scholar 

  39. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659–61.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Degen LA, Dorhout Mees SM, Algra A, Rinkel GJ. Interobserver variability of grading scales for aneurysmal subarachnoid hemorrhage. Stroke. 2011;42(6):1546–9.

    Article  PubMed  Google Scholar 

  42. Jaja BN, Attalla D, Macdonald RL, et al. The subarachnoid hemorrhage international trialists (SAHIT) repository: advancing clinical research in subarachnoid hemorrhage. Neurocrit Care. 2014;21(3):551–9.

    Article  PubMed  Google Scholar 

  43. 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.

    Article  PubMed  Google Scholar 

  44. Diringer MN, Bleck TP, Claude HJ 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.

    Article  PubMed  Google Scholar 

  45. Vergouwen MD, Vermeulen M, van GJ, 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.

  46. 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.

    Article  PubMed  Google Scholar 

  47. Macdonald RL, Higashida RT, Keller E, et al. Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care. 2010;13(3):416–24.

    Article  PubMed  Google Scholar 

  48. Ibrahim GM, Weidauer S, Vatter H, Raabe A, Macdonald RL. Attributing hypodensities on CT to angiographic vasospasm is not sensitive and unreliable. Stroke. 2012;43(1):109–12.

    Article  PubMed  Google Scholar 

  49. Vergouwen MD, Ilodigwe D, Macdonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke. 2011;42(4):924–9.

    Article  PubMed  Google Scholar 

  50. Klopfenstein JD, Spetzler RF, Kim LJ, et al. Comparison of routine and selective use of intraoperative angiography during aneurysm surgery: a prospective assessment. J Neurosurg. 2004;100(2):230–5.

    Article  PubMed  Google Scholar 

  51. Olson DM, Zomorodi M, Britz GW, Zomorodi AR, Amato A, Graffagnino C. Continuous cerebral spinal fluid drainage associated with complications in patients admitted with subarachnoid hemorrhage. J Neurosurg. 2013;119(4):974–80.

    Article  PubMed  Google Scholar 

  52. Brandt J, Spencer M, Folstein M. The telephone interval for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol. 1988;1:111–7.

    Google Scholar 

  53. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Med J. 1965;14:61–5.

    CAS  PubMed  Google Scholar 

  54. 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.

    Article  PubMed  Google Scholar 

  55. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–70.

    Article  CAS  PubMed  Google Scholar 

  56. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, Van GJ. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604–7.

    Article  PubMed  Google Scholar 

  57. Scott RB, Eccles F, Molyneux AJ, Kerr RS, Rothwell PM, Carpenter K. Improved cognitive outcomes with endovascular coiling of ruptured intracranial aneurysms: neuropsychological outcomes from the international subarachnoid aneurysm trial (ISAT). Stroke. 2010;41(8):1743–7.

    Article  PubMed  Google Scholar 

  58. Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41(8):e519–36.

    Article  PubMed  Google Scholar 

  59. Suarez JI, Martin RH. Treatment of subarachnoid hemorrhage with human albumin: ALISAH study. Rationale and design. Neurocrit Care. 2010;13(2):263–77.

    Article  CAS  PubMed  Google Scholar 

  60. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure): developed in collaboration with the international society for heart and lung transplantation; endorsed by the heart failure society of America. Circulation. 2001;104(24):2996–3007.

    Article  CAS  PubMed  Google Scholar 

  61. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev. 2004;23(4):223–38.

    Article  CAS  PubMed  Google Scholar 

  62. Van GJ, Hijdra A, Wijdicks EF, Vermeulen M, Van CH. Acute hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurosurg. 1985;63(3):355–62.

    Article  Google Scholar 

  63. Horan TC, Gaynes R. Surveillance of nosocomial infections. In: Mayhall CG, editor. Hospital epidemiology and infection control. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1659–702.

    Google Scholar 

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Conflict of interest

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 Chief Scientific Officer of Edge Therapeutics, Inc. Drs. Hänggi, Etminan, Aldrich, Mayer, Diringer, Hoh, and Mocco receive consulting fees from Edge Therapeutics, Inc. for serving on the steering committee for this trial and for advising Edge Therapeutics, Inc. Dr. Faleck is an employee of Edge Therapeutics, Inc. Drs. Strange and Miller are paid consultants for Edge Therapeutics, Inc.

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Correspondence to Daniel Hänggi.

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For the NEWTON Investigators.

Trial registration: www.clinicaltrials.gov Identifier: NCT01893190

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Hänggi, D., Etminan, N., Macdonald, R.L. et al. NEWTON: Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage. Neurocrit Care 23, 274–284 (2015). https://doi.org/10.1007/s12028-015-0112-2

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