Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis (ESCAPE-NEXT)

A Multicentre, Randomized, Double-blinded, Placebo-controlled, Parallel Group, Single-dose Design to Determine the Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis

The primary purpose of this study is to determine if a single dose of nerinetide can reduce global disability in people who have had a stroke and are selected for endovascular therapy without the use of a tissue plasminogen activator (alteplase, tenecteplase, or equivalent).

Study Overview

• Status: Completed
• Conditions: Stroke, Acute
• Intervention / Treatment: Drug: Placebo; Drug: Nerinetide

Detailed Description

This study is a Phase 3, randomized, multicentre, blinded, placebo-controlled, parallel group, single-dose with a single interim analysis. Because AIS (acute ischemic stroke) is a medical emergency, the trial is designed to enable the administration of standard-of-care treatments without delay in order to save the life of the person concerned, restore good health or alleviate suffering.

Participants harboring an acute ischemic stroke who are selected for endovascular revascularization without intravenous or intra-arterial thrombolytic therapy will be given a single, 2.6 mg/kg (up to a maximum dose of 270 mg) intravenous dose of nerinetide or placebo. Outcomes of the main trial will be evaluated throughout a 90 day observation period.

Participants will be followed at 1-Year for the analytic sub-trial for further outcome assessment by telemedicine or telephone interview conducted by individuals blinded to the outcome of the main trial. This sub-trial will be conducted to explore the independent functioning and quality of life at 1-Year.

• Study Type: Interventional
• Enrollment (Actual): 850
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Michael Tymianski, MD PhD; Phone Number: 4165831687; Email: mtymianski@nonoinc.ca
• Study Contact Backup: Name: Kathy Heard, MSc; Phone Number: 4165831687; Email: kheard@nonoinc.ca

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
  • Brisbane, Australia
    • Princess Alexandra Hospital
  • Clayton, Australia
    • Monash Medical Centre
  • Gold Coast, Australia
    • Gold Coast University Hospital
  • Murdoch, Australia
    • Fiona Stanley Hospital
  • Nedlands, Australia
    • Sir Charles Gairdner Hospital
  • Newcastle, Australia
    • John Hunter Hospital
  • Parkville, Australia
    • Royal Melbourne Hospital
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Medical Centre - University of Calgary
    • Edmonton, Alberta, Canada
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Vancouver General Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Queen Elizabeth II Health Science Centre
  • Ontario
    • Hamilton, Ontario, Canada
      • Hamilton Health Sciences
    • Kingston, Ontario, Canada
      • Kingston Health Sciences Centre
    • London, Ontario, Canada
      • London Health Sciences Centre (LHSC)
    • Ottawa, Ontario, Canada
      • Ottawa Hospital Research Institute (OHRI)
    • Toronto, Ontario, Canada
      • Toronto Western Hospital
    • Toronto, Ontario, Canada
      • Sunnybrook Health Science Centre
    • Toronto, Ontario, Canada
      • St. Michael's Hospital, Unity Health Toronto
  • Quebec
    • Montreal, Quebec, Canada
      • Montreal Neurological Institute and Hospital
    • Montreal, Quebec, Canada
      • University Hospital of Montreal
    • Quebec City, Quebec, Canada
      • CHU de Quebec-Universite Laval
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • Royal University Hospital
• Germany
  • Aachen, Germany
    • Universitätsklinikum RWTH Aachen
  • Altenburg, Germany
    • Klinikum Altenburger Land GmbH
  • Augsburg, Germany
    • Universitatsklinikum Augsburg
  • Bochum, Germany
    • Universitätsklinikum Knappschaftskrankenhaus Bochum
  • Bonn, Germany
    • Universitätsklinikum Bonn
  • Dortmund, Germany
    • Klinikum Dortmund gGmbH
  • Dresden, Germany
    • University of Dresden
  • Essen, Germany
    • Alfried-Krupp-Krankenhaus
  • Frankfurt, Germany
    • Universitätsklinikum Frankfurt
  • Freiburg, Germany
    • Universitätsklinikum Freiburg
  • Göttingen, Germany
    • Göttingen University Hospital
  • Hamburg, Germany
    • Universitatsklinikum Hamburg-Eppendorf
  • Heidelberg, Germany
    • Heidelberg University Hospital
  • Kiel, Germany
    • University Hospital Schleswig-Holstein
  • Leipzig, Germany
    • Universitätsklinikum Leipzig - Klinik und Poliklinik für Neurologie
  • München, Germany
    • Klinikum rechts der Isar Technical University of Munich
  • München, Germany
    • LMU Klinikum München
  • Münster, Germany
    • Universitätsklinikum Münster
  • Nürnberg, Germany
    • Nürnberg Hospital South Campus
  • Oldenburg, Germany
    • Evangelisches Krankenhaus Oldenburg
  • Stuttgart, Germany
    • Klinikum Stuttgart
  • Tübingen, Germany
    • Universitätsklinikum Tübingen
  • Würzburg, Germany
    • Würzburg University Hospital
• Italy
  • Bologna, Italy
    • Ospedale Maggiore di Bologna "Carlo Alberto Pizzardi"
  • Firenze, Italy
    • Azienda Ospedaliero Universitaria Careggi
  • Genoa, Italy
    • Ospedale Policlinico San Martino
  • Milan, Italy
    • Asst Grande Ospedale Metropolitano Niguarda
  • Napoli, Italy
    • Azienda Ospedaliera Antonio Cardarelli
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC
  • Maastricht, Netherlands
    • Maastricht University Medical Center
  • Rotterdam, Netherlands
    • Erasmus University Medical Center
• Norway
  • Oslo, Norway
    • Oslo University Hospital Ullevål
  • Oslo, Norway
    • Oslo University Hospital Rikshospitalet
  • Stavanger, Norway
    • Stavanger University Hospital
  • Tromsø, Norway
    • University Hospital of North-Norway
• Singapore
  • Singapore, Singapore
    • National University Hospital
  • Singapore, Singapore
    • National Neuroscience Institute
• Switzerland
  • Aarau, Switzerland
    • Kantonsspital Aarau
  • Basel, Switzerland
    • Universitätsspital Basel
  • Bern, Switzerland
    • Universitatsklinik fur Neurologie, Inselspital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital & Medical Center
  • California
    • Torrance, California, United States, 90503
      • Providence Little Company of Mary Medical Center - Torrance
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Swedish Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist Health Research Institute
    • Miami, Florida, United States, 33136
      • University of Miami, Jackson Memorial Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Brooklyn, New York, United States, 11220
      • NYU Langone Hospital Brooklyn
  • Ohio
    • Columbus, Ohio, United States, 43203
      • The Ohio State University, Wexner Medical Center Neurological Surgery
  • Oregon
    • Portland, Oregon, United States, 97225
      • Providence St. Vincent Medical Center
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Stroke Institute
  • Rhode Island
    • Providence, Rhode Island, United States, 02903-4923
      • Rhode Island Hospital
  • Texas
    • Harlingen, Texas, United States, 78550
      • Valley Baptist Medical Center - Harlingen
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center - Cherry Hill Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Acute ischemic stroke (AIS) selected for emergency endovascular treatment.
2. Age 18 years or greater.
3. Onset (last-known-well) time to randomization time within 12 hours.

4. Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS):

   1. NIHSS > 5 for internal carotid artery (ICA) and M1-middle cerebral artery (MCA) occlusion; or
   2. NIHSS > 10 for M2-MCA occlusion.
5. Confirmed symptomatic intracranial occlusion at one or more of the following locations: Intracranial carotid I/T/L, M1 or M2 segment MCA. Tandem extracranial carotid and intracranial occlusions are permitted.
6. Pre-stroke (24 hours prior to stroke onset) independent functional status in activities of daily living with modified Barthel Index (BI) ≥ 95. Patient must be living without requiring nursing care.
7. Qualifying imaging performed less than 2 hours prior to randomization.
8. Consent process completed as per national laws and regulation and the applicable ethics committee requirements.

Exclusion Criteria:

1. Treated with a tissue plasminogen activator (e.g., alteplase or tenecteplase) within 24 hours before randomization.
2. Determination by the treating physician, based on current treatment guidelines and medical evidence, that treatment with a plasminogen activator is indicated.
3. Large core of established infarction defined as ASPECTS 0-4.
4. Absent or poor collateral circulation on qualifying imaging (e.g. collateral score of 0 or 1).
5. Any intracranial hemorrhage on the qualifying imaging.
6. Planned use of an endovascular device not having approval or clearance by the relevant regulatory authority.
7. Endovascular thrombectomy procedure is completed as defined by the presence of TICI 2c/3 reperfusion or completion of groin / arterial closure.
8. Clinical history, past imaging or clinical judgment suggesting that the intracranial occlusion is chronic or there is suspected intracranial dissection such that there is a predicted lack of success with endovascular intervention.
9. Estimated or known weight > 120 kg (264 lbs).
10. Pregnancy/Lactation; female, with positive urine or serum beta human chorionic gonadotropin (β-hCG) test, or breastfeeding.
11. Known prior receipt of nerinetide for any reason, including prior enrolment in this ESCAPE-NEXT trial.
12. Severe known renal impairment defined as requiring renal replacement therapy (hemo- or peritoneal dialysis).
13. Severe or fatal comorbid illness that will prevent improvement or follow up.
14. Inability to complete follow-up treatment to Day 90.
15. Participation in another clinical trial investigating a drug, medical device, or a medical procedure in the 30 days preceding trial inclusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Vehicle only	Drug: Placebo; Vehicle only
Experimental: Nerinetide; Single intravenous infusion of nerinetide 2.6 mg/kg (up to a maximum dose of 270 mg) over 10 ± 1 minutes	Drug: Nerinetide; Single intravenous infusion of nerinetide 2.6 mg/kg (up to a maximum dose of 270 mg) over 10 ± 1 minutes; Other Names: NA-1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with independent functioning on the modified Rankin Scale (mRS), as defined by a score of 0-2	The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate, as defined by event rate (percent) for mortality over the 90-day study period.		90 days
Number of participants exhibiting a worsening of their index stroke.	Worsening of stroke is defined as (A) progression, or hemorrhagic transformation of the index stroke, as documented by medical imaging that is (a) life-threatening requiring intervention and/or (b) results in increased disability as gauged by a ≥4 point increase from lowest NIHSS during hospitalization or (B) results in death from the index stroke.	90 days
A shift of one or more categories to reduced functional dependence analyzed across the whole distribution of outcomes on the mRS at Day 90 post randomization.	The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.	90 days
Number of participants with good neurological outcome, as defined by a score of 0-2 on the NIHSS at Day 90 post randomization.	The National Institutes of Health Stroke Scale (NIHSS) is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity.	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of stroke as measured by MRI or CT brain imaging (MRI preferred)		90 days
Number of participants with functional independence in activities of daily living, as defined by a score of ≥ 95 on the Barthel Index (BI) at Day 90 post randomization.	The BI is an index of functional independence that is a valid measure of activities of daily living when employed in stroke trials. Modified BI scores range from 0 to 100, with higher scores indicating greater independence in activities of daily living and mobility.	90 days
Number of participants with reduced moderate or severe disability or death, as defined by a score of 4-6 on the mRS at Day 90 post randomization.	The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.	90 days
Number of participants with excellent functional outcome, as defined by a score of 0-1 on the mRS at Day 90 post randomization.	The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.	90 days
Health-related quality of life, as measured by the EQ-5D-5L at Day 90.	The EQ-5D-5L (EuroQol 5-Dimensional 5-Level) is a generic instrument for describing and valuing health. It is based on a descriptive system that defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has five response categories corresponding to: no problems, slight, moderate, severe and extreme problems. The respondents will also rate their overall health on the day of the interview on a 0-100 visual analogue scale (EQ-VAS, higher scores mean better outcomes).	90 days

Collaborators and Investigators

• Sponsor: NoNO Inc.
• Collaborators: University of Calgary
• Investigators: Principal Investigator: Michael D. Hill, MD MSc, Study Principal Investigator, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2020
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): August 31, 2023

Study Registration Dates

• First Submitted: July 2, 2020
• First Submitted That Met QC Criteria: July 2, 2020
• First Posted (Actual): July 8, 2020

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 8, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: NA-1-009

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No