Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke

Stroke, Acute Clinical Trial

— ESCAPE-NA1  

Official title:

A Multicentre, Randomized, Double-blinded, Placebo-controlled, Parallel Group, Single-dose Design to Determine the Efficacy and Safety of Intravenous NA-1 in Subjects With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02930018
• Other study ID #: NA-1-007
• Status: Completed
• Phase: Phase 3
• Start date: March 1, 2017
• Est. completion date: November 20, 2019

Study information

• Verified date: October 2022
• Source: NoNO Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The ESCAPE-NA-1 study is designed to determine the safety and efficacy of the neuroprotectant, Nerinetide (NA-1), in reducing global disability in subjects with major acute ischemic stroke (AIS) with a small established infarct core and with good collateral circulation who are selected for endovascular revascularization.

Description:

Trial Objectives: The primary objective is to determine the efficacy of the neuroprotectant, Nerinetide, in reducing global disability in subjects with major acute ischemic stroke (AIS) with a small established infarct core and with good collateral circulation selected for rapid endovascular revascularization. The secondary objectives are to determine the efficacy of Nerinetide in: - Reducing functional dependence - Improving neurological outcome - Improving activities of daily living - Reducing mortality rate The leading safety objectives are to determine the effect of administering a dose of 2.6 mg/kg (up to a maximum dose of 270 mg) intravenous (IV) infusion of Nerinetide to subject with acute stroke who are selected for endovascular revascularization on serious adverse events (SAEs) and 90-day mortality. Trial Design: This study is a Phase 3, randomized, multicentre, blinded, placebo-controlled, parallel group, single-dose design. Subjects harboring an acute ischemic stroke and who are selected for endovascular revascularization in accordance with local institutional practices and who harbor a small established infarct core and with good collateral circulation will be given a single, 2.6 mg/kg (up to a maximum dose of 270 mg) intravenous dose of Nerinetide (NA-1) or placebo as soon as they are deemed to have met the enrollment criteria and with the intention of starting administration within 30 minutes of randomization. The randomization will be by stochastic minimization to balance baseline factors.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1105
• Est. completion date: November 20, 2019
• Est. primary completion date: November 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Acute ischemic stroke (AIS) for immediate endovascular treatment

2. Age 18 or greater.

3. Onset (last-seen-well) time to randomization time within 12 hours.

4. Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS) > 5 at the time of randomization.

5. Pre-stroke (24 hours prior to stroke onset) independent functional status in activities of daily living with modified Barthel Index (BI) > 90 (95 or 100). Patient must be living in their own home, apartment or seniors lodge where no nursing care is required.

6. Confirmed symptomatic intracranial occlusion, based on multiphase or dynamic computerized tomographic angiography (CTA), at one or more of the following locations: Intracranial carotid T/L, M1 middle cerebral artery (MCA). Functionally, when defining the M1 or the M2, the bulk of the MCA territory must be ischemic.

7. Non-contrast computed tomography (NCCT) and CTA (multiphase or dynamic) for trial eligibility performed or repeated at ESCAPE-NA1 stroke centre with endovascular suite on-site.

8. Endovascular treatment with declared first endovascular approach as either stent retriever or aspiration device, and intended to be initiated (arterial access) within 60 minutes of baseline/qualifying NCCT and to first recanalization of 90 minutes. Study drug intended to be administered within 60 minutes of the baseline/qualifying NCCT.

9. Signed informed consent from subject or legally authorized representative or, if required to enable inclusion by applicable national laws and regulations and the applicable independent review boards/Ethics Committee requirements for obtaining consent, from the investigator after consultation with an independent physician who is not otherwise participating in the trial.

Exclusion Criteria:

1. Evidence of a large core of established infarction defined as ASPECTS 0-4.

2. Evidence of absence of collateral circulation on CTA (Collateral score of 0 or 1).

3. Intent to use any endovascular device other than a stent retriever or clot aspiration device or intra-arterial medications as the initial thrombectomy approach.

4. Intent to use any intravenous thrombolytic other than alteplase if intravenous thrombolysis is planned.

5. No femoral pulses, very difficult endovascular access or extreme tortuosity of great vessels that is predicted to result in an inability to deliver timely endovascular therapy. Direct common carotid or radial/brachial/axillary access is permissible.

6. Estimated or known weight > 120 kg or < 45 kg.

7. Pregnancy; if a woman is of childbearing potential a urine or serum beta human chorionic gonadotropin (ß-hCG) test is positive, or breastfeeding.

8. Severe contrast allergy or absolute contraindication to iodinated contrast preventing endovascular intervention, including any contraindications listed in the prescribing information approved by local authorities (e.g., patients with decompensated heart failure as a contraindication for the use of VISIPAQUE™ 270 in Germany).

9. Clinical history, past imaging or clinical judgment suggests that the intracranial occlusion is chronic or there is suspected intracranial dissection such that there is a predicted lack of success with endovascular intervention.

10. Prior enrolment in the ESCAPE-NA1 trial or prior receipt of NA-1 for any reason.

11. Severe known renal impairment defined as requiring dialysis (hemo- or peritoneal) or if known a creatinine clearance < 29 mL/min.

12. Patient has a severe or fatal comorbid illness that will prevent improvement or follow-up.

13. Patient cannot complete follow-up treatment due to co-morbid non-fatal illness or they are known to be a visitor to the city or any other known reason for which follow-up would be impossible (e.g. incarcerated in a federal prison).

14. Participation in another clinical trial investigating a drug, medical device, or a medical procedure in the 30 days preceding study inclusion.

Related Conditions & MeSH terms

• Stroke
• Stroke, Acute

Intervention

Drug:
• Nerinetide (NA-1), 2.6 mg/kg
Single intravenous infusion of nerinetide over 10 ± 1 minutes
• Placebo
Placebo Comparator: Placebo

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide
Australia	Royal Melbourne Hospital	Parkville
Canada	University of Calgary - Foothills Medical Centre	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Queen Elizabeth II Health Science Centre	Halifax	Nova Scotia
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre- University Hospital	London	Ontario
Canada	CHUM Hopital Notre-Dame	Montréal	Quebec
Canada	Montreal Neurological Institute and Hospital	Montréal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	CHU de Quebec- Universite Laval- Hopital de l'Enfant-Jesus	Quebec City	Quebec
Canada	Royal University Hospital	Saskatoon	Saskatchewan
Canada	St Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Centre	Toronto	Ontario
Canada	University Health Network - Toronto Western Hospital	Toronto	Ontario
Canada	Vancouver Stroke Program Research Office/ Vancouver General Hosptial	Vancouver	British Columbia
Germany	Universitätsklinikum Carl Gustav Carus Dresdner Neurovaskulares Centrum	Dresden
Germany	Klinik für Radiologie und Neuroradiologie	Essen
Germany	University Medical Center Goettingen	Göttingen
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Neurologische Klinik, Universität Heidelberg	Heidelberg
Ireland	Beaumont Hospital	Dublin
Ireland	Mater Hospital	Dublin
Korea, Republic of	Dongsan Medical Centre	Daegu
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Yonsei Univ, Severence	Seoul
Sweden	Skåne University Hospital	Lund
Sweden	Karolinksa Institutet	Stockholm
United Kingdom	Royal Victoria Hospital	Belfast
United States	Grady Memorial Hospital	Atlanta	Georgia
United States	NYU Lutheran Medical Center	Brooklyn	New York
United States	Chattanooga Center for Neurologic Research	Chattanooga	Tennessee
United States	Rush University Medical Center	Chicago	Illinois
United States	Riverside Radiology	Columbus	Ohio
United States	Swedish Medical Center	Englewood	Colorado
United States	Valley Baptist Medical Center	Harlingen	Texas
United States	Baptist Health Medical Center	Jacksonville	Florida
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	WellStar Health Systems	Marietta	Georgia
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Abington Memorial Hospital	Philadelphia	Pennsylvania
United States	UPMC Presbyterian	Pittsburgh	Pennsylvania
United States	Rhode Island Hospital	Providence	Rhode Island
United States	California Pacific Medical Center - Davies Campus	San Francisco	California
United States	Swedish Medical Center- Cherry Hill Campus	Seattle	Washington
United States	Providence Little Company of Mary Medical Center Torrance	Torrance	California
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina
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,  Ireland,  Korea, Republic of,  Sweden,  United Kingdom, 

References & Publications (8)

Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW, Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science. 2002 Oct 25;298(5594):846-50. — View Citation

Cook DJ, Teves L, Tymianski M. A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. Sci Transl Med. 2012 Oct 3;4(154):154ra133. doi: 10.1126/scitranslmed.3003824. — View Citation

Cook DJ, Teves L, Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature. 2012 Feb 29;483(7388):213-7. doi: 10.1038/nature10841. — View Citation

Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF, Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015 Mar 12;372(11):1019-30. doi: 10.1056/NEJMoa1414905. Epub 2015 Feb 11. — View Citation

Hill MD, Goyal M, Menon BK, Nogueira RG, McTaggart RA, Demchuk AM, Poppe AY, Buck BH, Field TS, Dowlatshahi D, van Adel BA, Swartz RH, Shah RA, Sauvageau E, Zerna C, Ospel JM, Joshi M, Almekhlafi MA, Ryckborst KJ, Lowerison MW, Heard K, Garman D, Haussen — View Citation

Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG, Milot G, Clark WM, Macdonald RL, Kelly ME, Boulton M, Fleetwood I, McDougall C, Gunnarsson T, Chow M, Lum C, Dodd R, Poublanc J, Krings T, Demchuk AM, Goyal M, Anderson R, Bishop J, Garman D, Tymianski M; ENACT trial investigators. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012 Nov;11(11):942-50. doi: 10.1016/S1474-4422(12)70225-9. Epub 2012 Oct 8. — View Citation

Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999 Jun 11;284(5421):1845-8. — View Citation

Sun HS, Doucette TA, Liu Y, Fang Y, Teves L, Aarts M, Ryan CL, Bernard PB, Lau A, Forder JP, Salter MW, Wang YT, Tasker RA, Tymianski M. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke. 2008 Sep;39(9):2544-53. doi: 10.1161/STROKEAHA.107.506048. Epub 2008 Jul 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With mRS Score of 0 to 2	Overall number of subjects experiencing a favorable functional outcome 90 days post-randomization, defined as 0 to 2 on the mRS.; 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 Subjects With NIHSS Score of 0 to 2	Number of subjects with good neurological outcome, as defined by a score of 0 to 2 on the NIHSS at Day 90 or the last rating.; 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 or the last rating
Secondary	Mortality Rate	Mortality rate, as defined by event rate (%) for mortality over the 90-day study period	90 Days