Clinical Trial Results:
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
(ESCAPE-NEXT Trial)
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Summary
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EudraCT number |
2020-002360-30 |
Trial protocol |
DE NO IT NL |
Global end of trial date |
19 Jun 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Aug 2024
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First version publication date |
11 Aug 2024
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Other versions |
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Summary report(s) |
ESCAPE-NEXT CSR Synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NA-1-009
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04462536 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
NoNO Inc.
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Sponsor organisation address |
333 Bay Street, Suite 2400, Toronto, Canada, M5H 2T6
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Public contact |
Yatika Kohli, NoNO Inc., +1 6473092950, ykohli@nonoinc.ca
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Scientific contact |
Michael Tymianski, NoNO Inc., +1 6472932232, mtymianski@nonoinc.ca
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Feb 2024
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Apr 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Jun 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective is to determine the efficacy of the neuroprotectant, nerinetide in:
• Reducing global disability in participants with acute ischemic
stroke (AIS)
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Protection of trial subjects |
Trial was carried out in accordance with the following local requirements in EU: EMEA EudraLex (Volume 4), the Rules Governing Medicinal Products in the European Union, EU Guidelines of Good Manufacturing Practices for Medicinal Products for Human and Veterinary Use and Eudralex (Volume 10), the Rules Governing Medicinal Products in the European Union, Clinical Trials Guidelines 2001/20/EC EU Clinical Trial Directives amended by Regulation (EC) No. 1901/2006 and Regulation (EC) No. 596/2009.
The ICF and the method for obtaining initial and regained capacity consent were approved by the local IEC/IRB prior to their implementation at each clinical site. All methods of conducting the informed consent process complied with ICH GCP E6. Information on how local privacy requirements (e.g., Europe GDPR) were addressed was incorporated as required either as a separate consent or within the ICF
Patient data was pseudo anonymized.
Participants were told that their participation was voluntary, and they could withdraw consent to participate at any time. Each participant or legally authorized representative (LAR) signed and dated an ICF after the nature of the trial had been fully explained and prior to performance of any trial-related activity.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
06 Dec 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 104
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Country: Number of subjects enrolled |
Germany: 197
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Country: Number of subjects enrolled |
Netherlands: 49
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Country: Number of subjects enrolled |
Norway: 18
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Country: Number of subjects enrolled |
Switzerland: 25
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Country: Number of subjects enrolled |
Canada: 303
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Country: Number of subjects enrolled |
Australia: 74
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Country: Number of subjects enrolled |
Singapore: 20
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Country: Number of subjects enrolled |
Italy: 60
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Worldwide total number of subjects |
850
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EEA total number of subjects |
324
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
194
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From 65 to 84 years |
489
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85 years and over |
167
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
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Pre-assignment
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Screening details |
Because AIS is a medical emergency, the trial was designed to enable the administration of standard-of-care treatments without delay in order to save the life of the person concerned. Adults >=18 years harboring an AIS who were selected for endovascular revascularization without intravenous (IV) or intra-arterial thrombolytic therapy were enrolled. | ||||||||||||||||||
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Period 1
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Period 1 title |
Main- 90 days (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Investigational | ||||||||||||||||||
Arm description |
Nerinetide | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Nerinetide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for solution for injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Single dose (2.6 mg/kg) via 10 min IV infusion
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Arm title
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Control | ||||||||||||||||||
Arm description |
Placebo-control arm | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Placebo consisted of the same buffer used for nerinetide with slightly higher NaCl content to adjust for equivalence of osmolality between drug product and placebo. It was supplied in identical 20 mL vials containing 13.5 mL of 50 mL sodium phosphate pH 7.0 (0.55% NaCl).
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Baseline characteristics reporting groups
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Reporting group title |
Main- 90 days
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Reporting group description |
- | |||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | |||||||||||||||||||||||||||||||||
Subject analysis set description |
All participants randomized into the trial with grouping by randomized treatment, regardless of treatment actually received. Participant grouped according to the randomized (intended) treatment.
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Subject analysis set title |
safety
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Subject analysis set type |
Safety analysis | |||||||||||||||||||||||||||||||||
Subject analysis set description |
All participants randomly assigned to study intervention and who receive any volume of study drug. Participants will be analyzed according to the intervention they actually received.
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End points reporting groups
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Reporting group title |
Investigational
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Reporting group description |
Nerinetide | ||
Reporting group title |
Control
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Reporting group description |
Placebo-control arm | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All participants randomized into the trial with grouping by randomized treatment, regardless of treatment actually received. Participant grouped according to the randomized (intended) treatment.
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Subject analysis set title |
safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All participants randomly assigned to study intervention and who receive any volume of study drug. Participants will be analyzed according to the intervention they actually received.
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End point title |
mRS Responder | ||||||||||||||||||||
End point description |
The proportion of participants with independent functioning on the modified Rankin Scale (mRS), as defined by a score of 0-2 at Day 90 post randomization.
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End point type |
Primary
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End point timeframe |
90 days post randomization
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Statistical analysis title |
mRS Responder Analysis | ||||||||||||||||||||
Comparison groups |
Investigational v Control
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Number of subjects included in analysis |
850
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
< 0.5 | ||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||
Point estimate |
0.959
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Confidence interval |
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95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.715 | ||||||||||||||||||||
upper limit |
1.288 | ||||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.782
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End point title |
Mortality Rate | ||||||||||||||||||||
End point description |
Mortality rates, defined as the number of deaths observed divided by the number of participants observed over the 90-day study period, were compared between nerinetide- and placebo-treated participants on the ITT population.
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End point type |
Secondary
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End point timeframe |
90 days post-randomization
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Worsening of Stroke | ||||||||||||||||||||
End point description |
Worsening of stroke was defined as (A) progression or hemorrhagic transformation of the index stroke as documented by medical imaging that was (a) life-threatening (requiring intervention) and/or (b) resulted in increased disability as gauged by a ≥4-point increase from lowest NIHSS during hospitalization OR (B) resulted in death from the index stroke.
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End point type |
Secondary
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End point timeframe |
90-days post-randomization
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| No statistical analyses for this end point | |||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
TEAEs occurring within 30 days of randomization and all SAEs up to Day 90 visit or death or until the participant was deemed “lost to follow-up” were reported. The safety population included all participants receiving any amount of study drug.
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Adverse event reporting additional description |
Frequencies are numbers of subjects experiencing at least one adverse event in that category. Subjects experiencing more than one adverse event in each category are counted only once for that category.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Nerinetide
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Reporting group description |
Safety assessments in the trial included the frequency of Treatment emergent adverse events (TEAEs), Serious Adverse events (SAEs) and discontinuations due to TEAEs. TEAEs occurring within 30 days of randomization and all SAEs up to the end of study visit (Day 90 visit or death) or until the participant was deemed “lost to follow-up” were reported. The safety population included all participants who received any amount of study drug. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Frequencies are numbers of subjects experiencing at least one adverse event in that category. Subjects experiencing more than one adverse event in each category are counted only once for that category | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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18 Nov 2021 |
- Updated Primary Analysis to adjust for Covariates
- altered the hierarchical testing order
- to remove collection of immunogenicity samples |
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01 Jun 2022 |
- Adaptive sample re-estimation design to more traditional group sequential design
- provide clarification of the handling of intercurrent events |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
