StrokePhase 1/2NCT04734548
Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke
A Phase 1/2 study testing ApTOLL in people with Stroke and Acute Stroke, run by aptaTargets S.L. at 16 sites in 3 countries.
Trial summary
This is a prospective, multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to assess the administration of ApTOLL together with endovascular therapy in acute ischemic stroke patients who are candidates to receive reperfusion therapies. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Stroke, Acute Stroke, Ischemic Stroke
- What is being tested?
- ApTOLL
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 151 participants
- Where
- 16 sitesin 3 countries
- Study dates
- 28 Oct 2020to 7 Sep 2022
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥18 and ≤90 years.
- Informed consent obtained from subject or acceptable subject surrogate (i.e. next of kin, or legal representative).
- A new focal disabling neurologic deficit consistent with acute cerebral ischemia.
- Baseline NIHSS obtained prior to randomization ≥ 8 points and ≤ 25 points.
- Pre-stroke mRS score of 0 - 2.
- Treatable as soon as possible and at least within 6 hours of symptom onset, defined as point in time when the subject was last seen well (at baseline).
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- Patients should be candidates to receive EVT treatment with or without i.v. rt-PA.
- Occlusion (TICI 0 or TICI 1 flow), of the terminal internal carotid artery (TICA), M1 or M2 segments of the middle cerebral artery, suitable for mechanical embolectomy, confirmed on Computed Tomography Angiography.
- The following imaging criteria should also be met on admission neuroimaging:
- MRI criterion: volume of DWI (Diffusion-weighted Imaging) restriction ≥5 mL and ≤70 mL OR
- CT criterion: Alberta Stroke program early CT score (ASPECTS) 6 to 10 on baseline CT AND infarct core determined on admission CTPerfusion by Cerebral Blood Flow<30%: ≥5 mL and ≤70 mL.
- The subject has an indication and is planned to receive endovascular treatment of stroke according to the European Stroke Organization Guidelines.
Who cannot join
- Subject has suffered a stroke in the past 1 year.
- Occlusion (TICI 0 or TICI 1 flow) of the basilar or vertebral or posterior or anterior cerebral arteries.
- Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories.
- Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR (international normalized ratio)>3.0.
- Baseline platelet count <50,000/μL.
- Baseline blood glucose of <50 mg/dL or >400 mg/dL.
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- Severe, sustained hypertension (systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg).
- Serious, advanced, or terminal illness with anticipated life expectancy of less than 1 year.
- Subjects with identifiable intracranial tumors.
- History of life-threatening allergy (more than rash) to contrast medium.
- Known renal insufficiency with creatinine ≥3 mg/dL or Glomerular Filtration Rate (GFR) <30 mL/min.
- Cerebral vasculitis.
- Evidence of active systemic infection.
- Known current use of cocaine at time of treatment.
- Patient participating in a study involving an investigational drug or device that would impact this study.
- Patients that are unlikely to be available for a 90-day follow-up (e.g. no fixed home address, visitor from overseas).
- Female who is pregnant or lactating or has a positive pregnancy test at time of admission.
- CT or MRI evidence of hemorrhage (the presence of microbleeds is allowed).
- Significant mass effect with midline shift.
- Suspicion of aortic dissection presumed septic embolus, or suspicion of bacterial endocarditis.
Trial locations and contacts
16 sites in 3 countries.
16 sites in 3 countries
Spain12 sites
Hospital Universitario A Coruña
A Coruña
Hospital Universitario Central de Asturias
Asturias
Hospital Bellvitge
Barcelona
Hospital Germans Trias i Pujol
Barcelona
Hospital Universitario Vall d´Hebron
Barcelona
Hospital Universitario de Gerona Dr. Josep Trueta
Girona
Hospital Universitario 12 de Octubre
Madrid
Hospital Universitario La Princesa
Madrid
Hospital Universitario Ramón y Cajal
Madrid
Hospital Virgen del Rocío
Seville
Hospital Universitario y Politécnico La Fe
Valencia
Hospital Clínico Valladolid
Valladolid
France3 sites
Centre Hospitalier Régional Universitaire de Lille
Lille
Foundation Adolphe de Rothschild
Paris
Centre Hospitalier Universitaire de Toulouse
Toulouse
About this study
Official title: A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke
This is a prospective, multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to assess the administration of ApTOLL together with endovascular therapy in acute ischemic stroke patients who are candidates to receive reperfusion therapies.
Read the detailed description
This is a prospective, multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to assess the administration of ApTOLL together with endovascular therapy in acute ischemic stroke (AIS) patients with confirmed Large Vessel Occlusion (LVO) who are candidates to receive reperfusion therapies including endovascular treatment with or without i.v. rt-PA (recombinant tissue Plasminogen Activator).
The study will be a Phase Ib/IIa trial where 2 doses selected, based on safety criteria, on Phase Ib will be administered in the following Phase IIa.The objective of the study is to evaluate if administration of ApTOLL at different doses is safe and well tolerated compared to placebo when administered with endovascular therapy (EVT), with or without i.v. rt-PA, in the AIS target population.
- Conditions
- Stroke, Acute Stroke, Ischemic Stroke
- Being tested
- ApTOLL, Placebo
- Medical subject headings
- Stroke, Ischemic Stroke
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ApTOLLDrug
ApTOLL is a Toll-like receptor 4 (TLR4) antagonist, a receptor that is involved in innate immune responses but also responds to tissue damage, and therefore it is directly involved in a large number of diseases where the inflammatory response is involved. ApTOLL has demonstrated specific binding to human TLR4 as well as a TLR4 antagonistic effect, reducing inflammation and improving outcome after different disease models.
PlaceboOther
White freeze-dried powder which is indistinguishable to ApTOLL for taste, color, texture and size.
| Study group | Role | What they receive |
|---|---|---|
| Phase Ib ApTOLL | Active comparator | ApTOLL is administered intravenously in a single ascending dose pattern in four dose levels (0.025mg/kg - 0.2mg/kg). All levels include six patients. Receives: Drug: ApTOLL |
| Phase Ib Placebo | Placebo comparator | Placebo is administered intravenously in a single ascending dose pattern in four dose levels (0.025mg/kg - 0.2mg/kg). All levels include two patients. Receives: Other: Placebo |
| Phase IIa ApTOLL | Active comparator | ApTOLL is administered intravenously (two doses selected in Phase Ib). The two dose levels include 35 patients each one. Receives: Drug: ApTOLL |
| Phase IIa Placebo | Placebo comparator | Placebo is administered intravenously in one arm which includes 49 patients. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety of ApTOLL
To assess if ApTOLL is safe when combined with EVT therapy as determined by:
- Death.
- Adverse events that occur during the study.
- Physical examination.
- Laboratory tests.
- Recurrent stroke.
- Symptomatic intracranial hemorrhage (sICH).
Measured: From dosing to follow-up (day 90 after dosing)
Secondary outcomes (4)
Mean infarct volume
Magnetic Resonance Image
Measured: 72 hours
Effect in inflammatory response
Proinflammatory markers in blood between study groups
Measured: Predose and up to 72 hours post-dose
Early clinical course
NIHSS (National institute of Health Stroke Scale). The maximum possible score is 42, with the minimum score being a 0 (the higher the score, the more impaired a stroke patient is)
Measured: 72 hours post-dose
Long-term outcome
mRS (modified Ranking Score). Coded from 0 (no symptoms at all) through 5 (severe disability) 6 (death).
Measured: Day 90 post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2021
- Study start28 Oct 2020
- Primary completion25 Jul 2022
- Study completion7 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for StrokeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 151 participants (actual)
Sponsor and investigators
- Lead sponsor
- aptaTargets S.L.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Ministry of Science and Innovation, Spain, Anagram
- Responsible party
- Sponsor
- Investigators
- Marc Ribó, MD, PhD, Study director, aptaTargets S.L.Macarena Hernández, PhD, Study director, aptaTargets S.L.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04734548
- Sponsor's protocol ID
- APRIL
- Status last verified
- Oct 2022
- First submitted
- 28 Jan 2021
- Last updated
- 21 Oct 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: All results obtained in this study will be published.
Publications
Hernandez-Jimenez M, Martin-Vilchez S, Ochoa D, Mejia-Abril G, Roman M, Camargo-Mamani P, Luquero-Bueno S, Jilma B, Moro MA, Fernandez G, Pineiro D, Ribo M, Gonzalez VM, Lizasoain I, Abad-Santos F. First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers. Mol Ther Nucleic Acids. 2022 Mar 9;28:124-135. doi: 10.1016/j.omtn.2022.03.005. eCollection 2022 Jun 14.
PubMed 35402075Hernandez-Jimenez M, Abad-Santos F, Cotgreave I, Gallego J, Jilma B, Flores A, Jovin TG, Vivancos J, Hernandez-Perez M, Molina CA, Montaner J, Casariego J, Dalsgaard M, Liebeskind DS, Cobo E, Castellanos M, Portela PC, Masjuan J, Moniche F, Tembl JI, Terceno Izaga M, Arenillas JF, Callejas P, Olivot JM, Calviere L, Henon H, Mazighi M, Pineiro D, Pugliese M, Gonzalez VM, Moro MA, Garcia-Tornel A, Lizasoain I, Ribo M. Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment: A Phase 1/2 Randomized Clinical Trial. JAMA Neurol. 2023 Aug 1;80(8):779-788. doi: 10.1001/jamaneurol.2023.1660.
PubMed 37338893Hernandez-Jimenez M, Abad-Santos F, Cotgreave I, Gallego J, Jilma B, Flores A, Jovin TG, Vivancos J, Molina CA, Montaner J, Casariego J, Dalsgaard M, Hernandez-Perez M, Liebeskind DS, Cobo E, Ribo M. APRIL: A double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke. Front Neurol. 2023 Feb 24;14:1127585. doi: 10.3389/fneur.2023.1127585. eCollection 2023.
PubMed 36908619Duran-Laforet V, Pena-Martinez C, Garcia-Culebras A, Alzamora L, Moro MA, Lizasoain I. Pathophysiological and pharmacological relevance of TLR4 in peripheral immune cells after stroke. Pharmacol Ther. 2021 Dec;228:107933. doi: 10.1016/j.pharmthera.2021.107933. Epub 2021 Jun 24.
PubMed 34174279
Study at a glance
From the registry record, last updated by the sponsor on 21 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke
- ClinicalTrials.gov ID
- NCT04734548
- Acronym / sponsor ID
- APRIL
- Conditions
- Stroke, Acute Stroke, Ischemic Stroke
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 151 participants (actual)
- Lead sponsor
- aptaTargets S.L.Industry (pharma, biotech, devices)
- Collaborators
- Ministry of Science and Innovation, Spain, Anagram
- Study start
- 28 Oct 2020 (actual)
- Primary completion
- 25 Jul 2022 (actual)
- Study completion
- 7 Sep 2022 (actual)
- First posted
- 2 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a prospective, multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to assess the administration of ApTOLL together with endovascular therapy in acute ischemic stroke patients who are candidates to receive reperfusion therapies.
Detailed description
This is a prospective, multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to assess the administration of ApTOLL together with endovascular therapy in acute ischemic stroke (AIS) patients with confirmed Large Vessel Occlusion (LVO) who are candidates to receive reperfusion therapies including endovascular treatment with or without i.v. rt-PA (recombinant tissue Plasminogen Activator).
The study will be a Phase Ib/IIa trial where 2 doses selected, based on safety criteria, on Phase Ib will be administered in the following Phase IIa.The objective of the study is to evaluate if administration of ApTOLL at different doses is safe and well tolerated compared to placebo when administered with endovascular therapy (EVT), with or without i.v. rt-PA, in the AIS target population.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Phase Ib ApTOLL | Active comparator | Drug: ApTOLLApTOLL is administered intravenously in a single ascending dose pattern in four dose levels (0.025mg/kg - 0.2mg/kg). All levels include six patients. |
| Phase Ib Placebo | Placebo comparator | Other: PlaceboPlacebo is administered intravenously in a single ascending dose pattern in four dose levels (0.025mg/kg - 0.2mg/kg). All levels include two patients. |
| Phase IIa ApTOLL | Active comparator | Drug: ApTOLLApTOLL is administered intravenously (two doses selected in Phase Ib). The two dose levels include 35 patients each one. |
| Phase IIa Placebo | Placebo comparator | Other: PlaceboPlacebo is administered intravenously in one arm which includes 49 patients. |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Age ≥18 and ≤90 years.
- Informed consent obtained from subject or acceptable subject surrogate (i.e. next of kin, or legal representative).
- A new focal disabling neurologic deficit consistent with acute cerebral ischemia.
- Baseline NIHSS obtained prior to randomization ≥ 8 points and ≤ 25 points.
- Pre-stroke mRS score of 0 - 2.
Key exclusion criteria (20 listed)
- Subject has suffered a stroke in the past 1 year.
- Occlusion (TICI 0 or TICI 1 flow) of the basilar or vertebral or posterior or anterior cerebral arteries.
- Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories.
- Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR (international normalized ratio)>3.0.
- Baseline platelet count <50,000/μL.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ApTOLLApTOLL is a Toll-like receptor 4 (TLR4) antagonist, a receptor that is involved in innate immune responses but also responds to tissue damage, and therefore it is directly involved in a large number of diseases where the inflammatory response is involved. ApTOLL has demonstrated specific binding to human TLR4 as well as a TLR4 antagonistic effect, reducing inflammation and improving outcome after different disease models. | Drug | Phase IIa ApTOLL, Phase Ib ApTOLL |
| PlaceboWhite freeze-dried powder which is indistinguishable to ApTOLL for taste, color, texture and size. | Other | Phase IIa Placebo, Phase Ib Placebo |
Primary outcome
Safety of ApTOLL
Time frame: From dosing to follow-up (day 90 after dosing)
To assess if ApTOLL is safe when combined with EVT therapy as determined by: 1. Death. 2. Adverse events that occur during the study. 3. Physical examination. 4. Laboratory tests. 5. Recurrent stroke. 6. Symptomatic intracranial hemorrhage (sICH).
4 secondary outcomes
Mean infarct volume
Time frame: 72 hours
Effect in inflammatory response
Time frame: Predose and up to 72 hours post-dose
Early clinical course
Time frame: 72 hours post-dose
Long-term outcome
Time frame: Day 90 post-dose
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Oct 2022.
- Background: PubMed 35402075Hernandez-Jimenez M, Martin-Vilchez S, Ochoa D, Mejia-Abril G, Roman M, Camargo-Mamani P, Luquero-Bueno S, Jilma B, Moro MA, Fernandez G, Pineiro D, Ribo M, Gonzalez VM, Lizasoain I, Abad-Santos F. First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers. Mol Ther Nucleic Acids. 2022 Mar 9;28:124-135. doi: 10.1016/j.omtn.2022.03.005. eCollection 2022 Jun 14.
- Derived from this study: PubMed 37338893Hernandez-Jimenez M, Abad-Santos F, Cotgreave I, Gallego J, Jilma B, Flores A, Jovin TG, Vivancos J, Hernandez-Perez M, Molina CA, Montaner J, Casariego J, Dalsgaard M, Liebeskind DS, Cobo E, Castellanos M, Portela PC, Masjuan J, Moniche F, Tembl JI, Terceno Izaga M, Arenillas JF, Callejas P, Olivot JM, Calviere L, Henon H, Mazighi M, Pineiro D, Pugliese M, Gonzalez VM, Moro MA, Garcia-Tornel A, Lizasoain I, Ribo M. Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment: A Phase 1/2 Randomized Clinical Trial. JAMA Neurol. 2023 Aug 1;80(8):779-788. doi: 10.1001/jamaneurol.2023.1660.
- Derived from this study: PubMed 36908619Hernandez-Jimenez M, Abad-Santos F, Cotgreave I, Gallego J, Jilma B, Flores A, Jovin TG, Vivancos J, Molina CA, Montaner J, Casariego J, Dalsgaard M, Hernandez-Perez M, Liebeskind DS, Cobo E, Ribo M. APRIL: A double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke. Front Neurol. 2023 Feb 24;14:1127585. doi: 10.3389/fneur.2023.1127585. eCollection 2023.
- Derived from this study: PubMed 34174279Duran-Laforet V, Pena-Martinez C, Garcia-Culebras A, Alzamora L, Moro MA, Lizasoain I. Pathophysiological and pharmacological relevance of TLR4 in peripheral immune cells after stroke. Pharmacol Ther. 2021 Dec;228:107933. doi: 10.1016/j.pharmthera.2021.107933. Epub 2021 Jun 24.
- Biotechnology company specialized in therapeutic aptamersLink provided by the sponsor.
- Individual participant dataSharing planned: No. All results obtained in this study will be published.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marc Ribó, MD, PhD study director
aptaTargets S.L.
Macarena Hernández, PhD study director
aptaTargets S.L.
16 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing ApTOLL in people with Stroke and Acute Stroke, run by aptaTargets S.L. at 16 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in Spain, France, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety of ApTOLL (time frame: From dosing to follow-up (day 90 after dosing)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04734548, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Oct 2022; AzTrials last refreshed its copy on 7 Nov 2026.