Field Randomization of Nerinetide (NA-1) Therapy in Early Responders (FRONTIER)

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of Intravenous NA-1 Initiated by Paramedics in the Field for Acute Cerebral Ischemia Within Three Hours of Symptom Onset

Brain Canada, Djavad Mowafaghian Centre for Brain Health, Canadian Stroke Network, University of Calgary, University of Toronto, University of British Columbia, Genome British Columbia

The purpose of this study is to determine whether nerinetide (NA-1) is effective in reducing global disability in patients with acute cerebral ischemia if administered early after symptom onset.

Nerinetide (NA-1) is being developed as an emergency drug aimed at reducing global disability in patients with acute cerebral ischemia if administered early after symptom onset. The primary objective is to determine the efficacy of nerinetide in reducing global disability in patients with acute stroke. The secondary objectives are to determine the efficacy of nerinetide in reducing functional dependence, reducing mortality rate, reducing worsening of stroke, improving neurological outcome and improving activities of daily living. The leading safety objectives are to determine the effect of administering a target dose of 2.60 mg/kg (up to a maximum dose of 270 mg) IV infusion of nerinetide within three hours of symptom onset by paramedics in the field on serious adverse events and 90-day mortality. This trial is a multicenter, randomized, double-blind, placebo-controlled, single dose study initiated prehospital in the ambulance. It is being conducted using Emergency Medical Services (EMS) in Canada. Subjects with suspected acute stroke will be identified in the field by trained paramedics using the approved stroke protocol in use by the local EMS system, and further screened for eligibility and approval by an on-call trial physician. The paramedics will administer the study drug. Upon arrival at the emergency department, subjects will receive standard-of-care. An Independent Data Monitoring Committee will perform safety reviews of the clinical data.

Stroke, Ischemia, Prehospital, NA-1, Modified Rankin Scale, Haemorrhagic stroke, Transient ischemic attack, Nerinetide

2.60 mg/kg of nerinetide (up to a maximum dose of 270 mg) administered as a single 10 minute IV infusion using an ambulatory infusion pump early after stroke symptom onset.

Placebo administered as a single 10 minute IV infusion using an ambulatory infusion pump early after stroke symptom onset.

A reduction in proportion of participants with worsening of stroke. Worsening of stroke is defined as progression, or hemorrhagic transformation, of the index stroke as documented in the study CRF that (i) is deemed life-threatening and/or (ii) results in increased disability as gauged by a ≥4 point increase from lowest NIHSS during hospitalization and/or (iii) results in death.

Proportion of subjects with functional independence in activities of daily living, as defined by a score of ≥ 95 on the Barthel Index

Inclusion Criteria: Provisional diagnosis of acute stroke as identified by paramedics using the local stroke triage tool Respiratory rate 12-24 breaths per minute Oxygen saturation ≥ 90% on room air Systolic blood pressure < 90 or > 220 mmHg Weight 45-120 kg Last seen in usual state of health less than 3 hours before anticipated study drug initiation Independently ambulatory with or without devices prior to event LAMS score of 2-5 for at least 15 minutes and remains 2-5 at time of randomization Exclusion Criteria: Lack of IV access Canadian Triage and Acuity Scale Level 1 and/or uncorrected airway, breathing or significant circulatory problem Blood sugar < 3 mmol/L (< 55 mg/dL) Seizure at onset of symptoms or observed by paramedic Glasgow coma score of <10 Major head trauma in the last three months Recent stroke in the last three months Known or presumptive signs of pregnancy or breastfeeding Prisoner Long term care facility resident Known advance directive to not resuscitate Known participation in a clinical trial with an investigational drug or device within 30 days preceding this trial Pre-existing neurologic, psychiatric, or advanced systemic condition that would preclude obtaining the neurological or functional outcome evaluations