Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis

Phase 3

Completed

• Conditions: Stroke, Acute
• Interventions: Drug: Placebo; Drug: Nerinetide

• Registration Number: NCT04462536
• Lead Sponsor: NoNO Inc.

Brief Summary

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).

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 Timeline

• Study First Submitted: 2020-07-02
• Study First Submitted QC: 2020-07-02
• Study First Posted: 2020-07-08
• Study Start: 2020-12-06
• Primary Completion: 2023-08-31
• Study Completion: 2023-08-31
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-08
• Last Update Posted: 2023-09-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 850

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Vehicle only
Nerinetide	Nerinetide	Single intravenous infusion of nerinetide 2.6 mg/kg (up to a maximum dose of 270 mg) over 10 ± 1 minutes

Primary Outcome Measures

Name	Time	Method
Number of participants with independent functioning on the modified Rankin Scale (mRS), as defined by a score of 0-2	90 days	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.

Secondary Outcome Measures

Name	Time	Method
Mortality rate, as defined by event rate (percent) for mortality over the 90-day study period.	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.	90 days	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.
Number of participants with good neurological outcome, as defined by a score of 0-2 on the NIHSS at Day 90 post randomization.	90 days	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.
Number of participants exhibiting a worsening of their index stroke.	90 days	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.

Trial Locations

Locations (81)

Kingston Health Sciences Centre; 🇨🇦 Kingston, Ontario, Canada

St. Michael's Hospital, Unity Health Toronto; 🇨🇦 Toronto, Ontario, Canada

Toronto Western Hospital; 🇨🇦 Toronto, Ontario, Canada

Grady Memorial Hospital; 🇺🇸 Atlanta, Georgia, United States

University of Maryland Medical Center; 🇺🇸 Baltimore, Maryland, United States

UPMC Stroke Institute; 🇺🇸 Pittsburgh, Pennsylvania, United States

Universitatsklinik fur Neurologie, Inselspital; 🇨🇭 Bern, Switzerland

Swedish Medical Center - Cherry Hill Campus; 🇺🇸 Seattle, Washington, United States

Monash Medical Centre; 🇦🇺 Clayton, Australia

Health Sciences Centre; 🇨🇦 Winnipeg, Manitoba, Canada

Ospedale Maggiore di Bologna "Carlo Alberto Pizzardi"; 🇮🇹 Bologna, Italy

University of Miami, Jackson Memorial Hospital; 🇺🇸 Miami, Florida, United States

St. Joseph's Hospital & Medical Center; 🇺🇸 Phoenix, Arizona, United States

Baptist Health Research Institute; 🇺🇸 Jacksonville, Florida, United States

The Ohio State University, Wexner Medical Center Neurological Surgery; 🇺🇸 Columbus, Ohio, United States

Valley Baptist Medical Center - Harlingen; 🇺🇸 Harlingen, Texas, United States

Providence St. Vincent Medical Center; 🇺🇸 Portland, Oregon, United States

Abington Memorial Hospital; 🇺🇸 Abington, Pennsylvania, United States

Royal Adelaide Hospital; 🇦🇺 Adelaide, Australia

Gold Coast University Hospital; 🇦🇺 Gold Coast, Australia

Princess Alexandra Hospital; 🇦🇺 Brisbane, Australia

Fiona Stanley Hospital; 🇦🇺 Murdoch, Australia

Royal Melbourne Hospital; 🇦🇺 Parkville, Australia

Sir Charles Gairdner Hospital; 🇦🇺 Nedlands, Australia

John Hunter Hospital; 🇦🇺 Newcastle, Australia

Foothills Medical Centre - University of Calgary; 🇨🇦 Calgary, Alberta, Canada

University of Alberta Hospital; 🇨🇦 Edmonton, Alberta, Canada

Vancouver General Hospital; 🇨🇦 Vancouver, British Columbia, Canada

Queen Elizabeth II Health Science Centre; 🇨🇦 Halifax, Nova Scotia, Canada

Ottawa Hospital Research Institute (OHRI); 🇨🇦 Ottawa, Ontario, Canada

London Health Sciences Centre (LHSC); 🇨🇦 London, Ontario, Canada

Hamilton Health Sciences; 🇨🇦 Hamilton, Ontario, Canada

Sunnybrook Health Science Centre; 🇨🇦 Toronto, Ontario, Canada

Montreal Neurological Institute and Hospital; 🇨🇦 Montreal, Quebec, Canada

CHU de Quebec-Universite Laval; 🇨🇦 Quebec City, Quebec, Canada

University Hospital of Montreal; 🇨🇦 Montreal, Quebec, Canada

Universitätsklinikum RWTH Aachen; 🇩🇪 Aachen, Germany

Klinikum Altenburger Land GmbH; 🇩🇪 Altenburg, Germany

Royal University Hospital; 🇨🇦 Saskatoon, Saskatchewan, Canada

Universitätsklinikum Augsburg; 🇩🇪 Augsburg, Germany

Universitätsklinikum Knappschaftskrankenhaus Bochum; 🇩🇪 Bochum, Germany

Alfried-Krupp-Krankenhaus; 🇩🇪 Essen, Germany

Universitätsklinikum Bonn; 🇩🇪 Bonn, Germany

Klinikum Dortmund gGmbH; 🇩🇪 Dortmund, Germany

University of Dresden; 🇩🇪 Dresden, Germany

Universitätsklinikum Freiburg; 🇩🇪 Freiburg, Germany

Göttingen University Hospital; 🇩🇪 Göttingen, Germany

Heidelberg University Hospital; 🇩🇪 Heidelberg, Germany

Universitätsklinikum Frankfurt; 🇩🇪 Frankfurt, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

University Hospital Schleswig-Holstein; 🇩🇪 Kiel, Germany

LMU Klinikum München; 🇩🇪 München, Germany

Universitätsklinikum Leipzig - Klinik und Poliklinik für Neurologie; 🇩🇪 Leipzig, Germany

Klinikum rechts der Isar Technical University of Munich; 🇩🇪 München, Germany

Universitätsklinikum Münster; 🇩🇪 Münster, Germany

Nürnberg Hospital South Campus; 🇩🇪 Nürnberg, Germany

Evangelisches Krankenhaus Oldenburg; 🇩🇪 Oldenburg, Germany

Würzburg University Hospital; 🇩🇪 Würzburg, Germany

Klinikum Stuttgart; 🇩🇪 Stuttgart, Germany

Universitätsklinikum Tübingen; 🇩🇪 Tübingen, Germany

Azienda Ospedaliero Universitaria Careggi; 🇮🇹 Firenze, Italy

Ospedale Policlinico San Martino; 🇮🇹 Genoa, Italy

ASST Grande Ospedale Metropolitano Niguarda; 🇮🇹 Milan, Italy

Azienda Ospedaliera Antonio Cardarelli; 🇮🇹 Napoli, Italy

Amsterdam UMC; 🇳🇱 Amsterdam, Netherlands

Maastricht University Medical Center; 🇳🇱 Maastricht, Netherlands

Erasmus University Medical Center; 🇳🇱 Rotterdam, Netherlands

Oslo University Hospital Rikshospitalet; 🇳🇴 Oslo, Norway

Oslo University Hospital Ulleval; 🇳🇴 Oslo, Norway

Stavanger University Hospital; 🇳🇴 Stavanger, Norway

University Hospital of North-Norway; 🇳🇴 Tromsø, Norway

Universitätsspital Basel; 🇨🇭 Basel, Switzerland

National Neuroscience Institute; 🇸🇬 Singapore, Singapore

National University Hospital; 🇸🇬 Singapore, Singapore

Kantonsspital Aarau; 🇨🇭 Aarau, Switzerland

Providence Little Company of Mary Medical Center - Torrance; 🇺🇸 Torrance, California, United States

University of Massachusetts Medical School; 🇺🇸 Worcester, Massachusetts, United States

NYU Langone Hospital Brooklyn; 🇺🇸 Brooklyn, New York, United States

Swedish Medical Center; 🇺🇸 Englewood, Colorado, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States