title: NEWTON: Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Moorenstraße 5, 40225, Düsseldorf, Germany, daniel.haenggi@uni-duesseldorf.de.
authors: Daniel
authors: D
authors: Hänggi
authors: Nima
authors: N
authors: Etminan
authors: R Loch
authors: RL
authors: Macdonald
authors: Hans Jakob
authors: HJ
authors: Steiger
authors: Stephan A
authors: SA
authors: Mayer
authors: Francois
authors: F
authors: Aldrich
authors: Michael N
authors: MN
authors: Diringer
authors: Brian L
authors: BL
authors: Hoh
authors: J
authors: J
authors: Mocco
authors: Poul
authors: P
authors: Strange
authors: Herbert J
authors: HJ
authors: Faleck
authors: Michael
authors: M
authors: Miller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017542:Aneurysm, Ruptured / Q000150:complications; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002985:Clinical Protocols; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D057967:Infusions, Intraventricular; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic / Q000379:methods*; D009553:Nimodipine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D017063:Outcome Assessment, Health Care / Q000379:methods*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000209:etiology; D055815:Young Adult
chemical_list: D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D009553:Nimodipine