Clinical Trial Results:
A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke
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Summary
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EudraCT number |
2020-002059-38 |
Trial protocol |
FR DE PT |
Global end of trial date |
22 Jul 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Oct 2023
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First version publication date |
08 Oct 2023
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Other versions |
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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 |
APRIL
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04734548 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AptaTargets S.L.
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Sponsor organisation address |
Av. Cardenal Herrera Oria 298, Madrid, Spain, 28035
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Public contact |
CFO and Legal Manager, AptaTargets S.L, 34 34910568359, m.zarabozo@aptatargets.com
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Scientific contact |
Associate Professor, AptaTargets S.L, 34 910568359, m.hernandez@aptatargets.com
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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 |
22 Jul 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Jul 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Jul 2022
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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 evaluate if administering ApTOLL intravenously (IV) at ascending doses is safe and well tolerated compared to placebo when administered with endovascular therapy (EVT) ± IV recombinant tissue Plasminogen Activator (rt-PA) in the acute ischemic stroke (AIS) target population.
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Protection of trial subjects |
Prior to the dosing, patients and/or legal representatives must receive oral and written information concerning the study. If they subsequently agree to participate, they or their legal representatives must sign the informed consent form, under the awareness of their ability to withdraw from the study at any time and for any reason.
The subjects will receive instructions from the investigators which must be followed strictly. Informed consent must be signed by the patient or their authorized legal representative before any study specific treatment is performed.
Patients will receive standard ESO guidelines directed medical therapy, which can include IV rt-PA infusion in patients presenting within the first 4.5 hours from last-seen-normal and meeting other ESO label criteria. Post-tPA patients will be treated based on standard study site protocols for these patients.
In all patients, endovascular thrombectomy will be initiated (groin puncture) after randomization and administration of the study drug. EVT should be initiated within 8 hours from symptoms onset. Individual investigators may use any approved device or any combination of devices to remove thrombus. If there is severe stenosis of the common carotid artery or the proximal internal carotid artery, investigators may also use devices for angioplasty or for stenting of the carotid artery as deemed appropriate.
The study will be conducted in accordance with legal normative and regulations, and with the general principles outlined in the International Ethical Guidelines for Biomedical research in humans. In addition, the study will be performed according to the protocol, GCP guideline and the ICH requirements and applicable local laws.
Any individual patient or family member complaints regarding adverse events or morbidity will be handled locally by each institution’s patient safety centre.
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Background therapy |
EVT ± IV recombinant tissue Plasminogen Activator (rt-PA) | ||
Evidence for comparator |
Standard of Care | ||
Actual start date of recruitment |
07 Nov 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Spain: 143
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Country: Number of subjects enrolled |
France: 8
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Worldwide total number of subjects |
151
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EEA total number of subjects |
151
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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) |
44
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From 65 to 84 years |
86
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85 years and over |
21
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Recruitment
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Recruitment details |
The first patient was included in the study on November 7, 2020. The last patient was included on April 22, 2022. The last patient last visit was completed on July 22, 2022. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Men and non-pregnant women with confirmed Acute Ischemic Stroke with Large Vessel Occlusion in the anterior circulation, defined as per EU-US guidelines, with a <6h window from onset of symptoms to drug administration, who were candidates to receive EVT treatment. | ||||||||||||||||||
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Period 1
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Period 1 title |
Phase Ib & IIa (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 | ||||||||||||||||||
Blinding implementation details |
In Phase Ib, four dose levels were performed, and eligible patients were randomized into ApTOLL plus EVT vs. Placebo plus EVT at 3:1 ratio, at every dose level.
In Phase IIa the randomization algorithm followed the Dunnet’s random allocation procedure of square root (number of groups - 1), which assigns patients with the following frequency to placebo, active A and active B: √2 :1:1, which, in turn, yields a probability of assignment of 0.41, 0.29 and 0.29, respectively.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ApTOLL | ||||||||||||||||||
Arm description |
Phase Ib: ApTOLL (0.025 – 0.2 mg/Kg) 30min IV infusion. Phase IIa: ApTOLL (0.05 mg/Kg [Dose A] and 0.2 mg/Kg [Dose B]) 30min IV infusion. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
ApTOLL
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Investigational medicinal product code |
PRD10291571
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Other name |
Aptamer 4FT
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
One single 30 min IV infusion prior to thrombectomy.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Phase Ib & IIa: Placebo 30min IV infusion. | ||||||||||||||||||
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 |
Powder for solution for infusion
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Routes of administration |
Intracavernous use
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Dosage and administration details |
One single 30 min IV infusion prior to thrombectomy.
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Baseline characteristics reporting groups
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Reporting group title |
ApTOLL
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Reporting group description |
Phase Ib: ApTOLL (0.025 – 0.2 mg/Kg) 30min IV infusion. Phase IIa: ApTOLL (0.05 mg/Kg [Dose A] and 0.2 mg/Kg [Dose B]) 30min IV infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Phase Ib & IIa: Placebo 30min IV infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ApTOLL
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Reporting group description |
Phase Ib: ApTOLL (0.025 – 0.2 mg/Kg) 30min IV infusion. Phase IIa: ApTOLL (0.05 mg/Kg [Dose A] and 0.2 mg/Kg [Dose B]) 30min IV infusion. | ||
Reporting group title |
Placebo
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Reporting group description |
Phase Ib & IIa: Placebo 30min IV infusion. | ||
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End point title |
Death | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline-Day 90
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Statistical analysis title |
ApTOLL vs Placebo | |||||||||
Comparison groups |
ApTOLL v Placebo
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Number of subjects included in analysis |
151
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
t-test, 2-sided | |||||||||
Confidence interval |
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End point title |
All AEs | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline-Day 90
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Statistical analysis title |
ApTOLL vs Placebo | |||||||||
Comparison groups |
ApTOLL v Placebo
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Number of subjects included in analysis |
151
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
t-test, 2-sided | |||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 to Day 90
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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 |
25.0
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Reporting groups
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Reporting group title |
ApTOLL
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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13 Oct 2020 |
To include the NIHSS determination at Day 5 after randomization. |
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22 Jan 2021 |
v3.0 (France) To update the Stopping Rules of the trial after updating the DSMB charter.
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23 Feb 2021 |
v2.1 (Germany) To update the Stopping Rules of the trial after updating the DSMB charter. |
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21 May 2021 |
v4.0 (Spain): To update the Stopping Rules of the trial after updating the DSMB charter. |
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21 May 2021 |
v4.0 (Spain)
To define the times to obtain samples for biomarker determination in Phase IIa.
To add an image substudy in some sites at Day 90 after randomization.
To add a new subestudy to determine biomarkers in some sites.
To modify exclusion criterium 9: Subjects with identifiable intracerebral tumors (meningioma is considered extracerebral tumor, so it is not included in this exclusion criterium). |
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01 Jun 2021 |
v3.2 (France)
To define the times to obtain samples for biomarker determination in Phase IIa.
To add an image substudy in some sites at Day 90 after randomization.
To add a new subestudy to determine biomarkers in some sites.
To modify exclusion criterium 9: Subjects with identifiable intracerebral tumors (meningioma is considered extracerebral tumor, so it is not included in this exclusion criterium). |
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21 Jun 2021 |
v3.0 (Germany)
To define the times to obtain samples for biomarker determination in Phase IIa.
To add an image substudy in some sites at Day 90 after randomization.
To add a new subestudy to determine biomarkers in some sites.
To modify exclusion criterium 9: Subjects with identifiable intracerebral tumors (meningioma is considered extracerebral tumor, so it is not included in this exclusion criterium). |
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06 Oct 2021 |
v3.0 (Portugal):
To update the Stopping Rules of the trial after updating the DSMB charter.
To define the times to obtain samples for biomarker determination in Phase IIa.
To add an image substudy in some sites at Day 90 after randomization.
To add a new subestudy to determine biomarkers in some sites.
To modify exclusion criterium 9: Subjects with identifiable intracerebral tumors (meningioma is considered extracerebral tumor, so it is not included in this exclusion criterium). |
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11 Oct 2021 |
v4.0 (France): To modify the inclusion criterium 1: Age ≥18 and ≤85 years to Age ≥18 and ≤90 years.
To define the timing to include patients with wake-up strokes |
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11 Oct 2021 |
v4.0 (Germany): To modify the inclusion criterium 1: Age ≥18 and ≤85 years to Age ≥18 and ≤90 years. To define the timing to include patients with wake-up strokes |
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11 Oct 2021 |
v5.0 (Spain): To modify the inclusion criterium 1: Age ≥18 and ≤85 years to Age ≥18 and ≤90 years. To define the timing to include patients with wake-up strokes |
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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 | |||
