Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1)

• ClinicalTrials.gov Identifier: NCT02930018
• Recruitment Status: Completed
• First Posted: October 11, 2016
• Results First Posted: December 14, 2020
• Last Update Posted: October 10, 2022
• Sponsor: NoNO Inc.
• Collaborator: University of Calgary
• Information provided by (Responsible Party): NoNO Inc.

Tracking Information

• First Submitted Date: October 6, 2016
• First Posted Date: October 11, 2016
• Results First Submitted Date: October 22, 2020
• Results First Posted Date: December 14, 2020
• Last Update Posted Date: October 10, 2022
• Actual Study Start Date: March 1, 2017
• Actual Primary Completion Date: November 20, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 18, 2020)

Number of Subjects With mRS Score of 0 to 2 [ Time Frame: 90 Days ]

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.

Original Primary Outcome Measures (submitted: October 7, 2016)

Modified Rankin Score (mRS) [ Time Frame: 90 Days ]

Overall proportion of subjects experiencing a favorable functional outcome 90 days post-randomization, defined as 0 to 2 on the mRS

Current Secondary Outcome Measures (submitted: November 18, 2020)

• Number of Subjects With NIHSS Score of 0 to 2 [ Time Frame: 90 Days or the last rating ]
  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.
• Mortality Rate [ Time Frame: 90 Days ]
  Mortality rate, as defined by event rate (%) for mortality over the 90-day study period

Original Secondary Outcome Measures (submitted: October 7, 2016)

• mRS Shift Analysis [ Time Frame: 90 Days or the last rating ]
  Shift of one or more categories to reduced functional dependence analyzed across the whole distribution of scores on the mRS at Day 90 or the last rating.
• NIHSS [ Time Frame: 90 Days or the last rating ]
  Proportion of subjects with good neurological outcome, as defined by a score of 0-2 on the NIHSS at Day 90 or the last rating.
• Barthel Index [ Time Frame: 90 Days or the last rating ]
  Proportion of subjects with functional independence in activities of daily living, as defined by a score of ≥ 95 on the BI at Day 90 or the last rating.
• Mortality Rate [ Time Frame: 90 Days ]
  A reduction in mortality rate, as defined by event rate (%) for mortality over the 90-day study period
• Functional Independence based on mRS [ Time Frame: 90 Days or the last rating ]
  Proportion of subjects with functional independence, as defined by a score of 0-1 on the mRS at Day 90 or the last rating.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: October 7, 2016)

• EQ-5D-5L [ Time Frame: 90 Days or the last rating ]
  Health-related quality of life, as measured by the EQ-5D-5L at Day 90 or the last rating.
• Stroke Volume [ Time Frame: 24 hour follow up ]
  Volume of stroke as measured by MRI. If NCCT was done instead of MRI, Volume of stroke will be derived from hypodense areas.
• Test of language function [ Time Frame: 90 Days ]
  Cognitive outcome - The 15-item Boston Naming Test (BNT15)
• Test of hemi-spatial neglect [ Time Frame: 90 Days ]
  Cognitive Outcome - Sunnybrook hemi-spatial neglect procedure (SNAP)
• Global test of cognitive function. Scale from 0 to 30 points. [ Time Frame: 90 Days ]
  Cognitive outcome - The Montreal Cognitive Assessment (MoCA)
• Functional outcome based on mRS [ Time Frame: 30 days ]
  The proportion of subjects experiencing a favorable functional outcome 30 days post-randomization, defined as 0 to 2 on the mRS.

Descriptive Information

• Brief Title: Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke
• 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
• Brief 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.

Detailed 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Stroke, Acute

Intervention

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

Study Arms

• Placebo Comparator: Placebo
  Drug vehicle only
  Intervention: Drug: Placebo
• Experimental: Nerinetide (NA-1), 2.6 mg/kg
  Intervention: Drug: Nerinetide (NA-1), 2.6 mg/kg

Publications *

• 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.
• 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.
• 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.
• 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.
• 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. doi: 10.1126/science.1072873.
• 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. doi: 10.1126/science.284.5421.1845.
• 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.
• 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 D, Cutting SM, Coutts SB, Roy D, Rempel JL, Rohr AC, Iancu D, Sahlas DJ, Yu AYX, Devlin TG, Hanel RA, Puetz V, Silver FL, Campbell BCV, Chapot R, Teitelbaum J, Mandzia JL, Kleinig TJ, Turkel-Parrella D, Heck D, Kelly ME, Bharatha A, Bang OY, Jadhav A, Gupta R, Frei DF, Tarpley JW, McDougall CG, Holmin S, Rha JH, Puri AS, Camden MC, Thomalla G, Choe H, Phillips SJ, Schindler JL, Thornton J, Nagel S, Heo JH, Sohn SI, Psychogios MN, Budzik RF, Starkman S, Martin CO, Burns PA, Murphy S, Lopez GA, English J, Tymianski M; ESCAPE-NA1 Investigators. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet. 2020 Mar 14;395(10227):878-887. doi: 10.1016/S0140-6736(20)30258-0. Epub 2020 Feb 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 16, 2020): 1105
• Original Estimated Enrollment (submitted: October 7, 2016): 1120
• Actual Study Completion Date: November 20, 2019
• Actual Primary Completion Date: November 20, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 (β-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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Germany, Ireland, Korea, Republic of, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02930018
• Other Study ID Numbers: NA-1-007
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: NoNO Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: NoNO Inc.
• Original Study Sponsor: Same as current
• Collaborators: University of Calgary

Investigators

• Principal Investigator: Michael D Hill, MD MSc; University of Calgary

• PRS Account: NoNO Inc.
• Verification Date: October 2022