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

Stroke, Acute Clinical Trial

— ESCAPE-NEXT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04462536
• Other study ID #: NA-1-009
• Status: Completed
• Phase: Phase 3
• Start date: December 6, 2020
• Est. completion date: August 31, 2023

Study information

• Verified date: September 2023
• Source: NoNO Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 850
• Est. completion date: August 31, 2023
• Est. primary completion date: August 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (ß-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.

Related Conditions & MeSH terms

• Ischemic Stroke
• Stroke
• Stroke, Acute

Intervention

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

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
NoNO Inc.	University of Calgary

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Germany,  Italy,  Netherlands,  Norway,  Singapore,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Volume of stroke as measured by MRI or CT brain imaging (MRI preferred)		90 days
Other	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
Other	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
Other	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
Other	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
Primary	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	Mortality rate, as defined by event rate (percent) for mortality over the 90-day study period.		90 days
Secondary	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
Secondary	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
Secondary	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