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Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke

Primary Purpose

Stroke, Acute Stroke, Ischemic Stroke

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ApTOLL
Placebo
Sponsored by
aptaTargets S.L.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stroke

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥18 and ≤90 years.
  2. Informed consent obtained from subject or acceptable subject surrogate (i.e. next of kin, or legal representative).
  3. A new focal disabling neurologic deficit consistent with acute cerebral ischemia.
  4. Baseline NIHSS obtained prior to randomization ≥ 8 points and ≤ 25 points.
  5. Pre-stroke mRS score of 0 - 2.
  6. 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).
  7. Patients should be candidates to receive EVT treatment with or without i.v. rt-PA.
  8. 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.

  9. The following imaging criteria should also be met on admission neuroimaging:

    1. MRI criterion: volume of DWI (Diffusion-weighted Imaging) restriction ≥5 mL and ≤70 mL OR
    2. 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.
  10. The subject has an indication and is planned to receive endovascular treatment of stroke according to the European Stroke Organization Guidelines.

Exclusion Criteria:

  1. Subject has suffered a stroke in the past 1 year.
  2. Occlusion (TICI 0 or TICI 1 flow) of the basilar or vertebral or posterior or anterior cerebral arteries.
  3. Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories.
  4. Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR (international normalized ratio)>3.0.
  5. Baseline platelet count <50,000/μL.
  6. Baseline blood glucose of <50 mg/dL or >400 mg/dL.
  7. Severe, sustained hypertension (systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg).
  8. Serious, advanced, or terminal illness with anticipated life expectancy of less than 1 year.
  9. Subjects with identifiable intracranial tumors.
  10. History of life-threatening allergy (more than rash) to contrast medium.
  11. Known renal insufficiency with creatinine ≥3 mg/dL or Glomerular Filtration Rate (GFR) <30 mL/min.
  12. Cerebral vasculitis.
  13. Evidence of active systemic infection.
  14. Known current use of cocaine at time of treatment.
  15. Patient participating in a study involving an investigational drug or device that would impact this study.
  16. Patients that are unlikely to be available for a 90-day follow-up (e.g. no fixed home address, visitor from overseas).
  17. Female who is pregnant or lactating or has a positive pregnancy test at time of admission.
  18. CT or MRI evidence of hemorrhage (the presence of microbleeds is allowed).
  19. Significant mass effect with midline shift.
  20. Suspicion of aortic dissection presumed septic embolus, or suspicion of bacterial endocarditis.

Sites / Locations

  • Centre Hospitalier Régional Universitaire de Lille
  • Foundation Adolphe de Rothschild
  • Centre Hospitalier Universitaire de Toulouse
  • Universitätsklinikum Essen
  • Hospital Universitario Central de Asturias
  • Hospital Bellvitge
  • Hospital Germans Trias i Pujol
  • Hospital Universitario Vall d´Hebron
  • Hospital Universitario A Coruña
  • Hospital Universitario de Gerona Dr. Josep Trueta
  • Hospital Universitario 12 de Octubre
  • Hospital Universitario La Princesa
  • Hospital Universitario Ramón y Cajal
  • Hospital Virgen del Rocío
  • Hospital Universitario y Politécnico La Fe
  • Hospital Clínico Valladolid

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

Phase Ib ApTOLL

Phase Ib Placebo

Phase IIa ApTOLL

Phase IIa Placebo

Arm Description

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.

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.

ApTOLL is administered intravenously (two doses selected in Phase Ib). The two dose levels include 35 patients each one.

Placebo is administered intravenously in one arm which includes 49 patients.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Mean infarct volume
Magnetic Resonance Image
Effect in inflammatory response
Proinflammatory markers in blood between study groups
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)
Long-term outcome
mRS (modified Ranking Score). Coded from 0 (no symptoms at all) through 5 (severe disability) 6 (death).

Full Information

First Posted
January 28, 2021
Last Updated
October 19, 2022
Sponsor
aptaTargets S.L.
Collaborators
Science and Innovation Spanish Ministry, Anagram
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1. Study Identification

Unique Protocol Identification Number
NCT04734548
Brief Title
Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke
Official Title
A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
October 28, 2020 (Actual)
Primary Completion Date
July 25, 2022 (Actual)
Study Completion Date
September 7, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
aptaTargets S.L.
Collaborators
Science and Innovation Spanish Ministry, Anagram

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stroke, Acute Stroke, Ischemic Stroke

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
151 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase Ib ApTOLL
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Phase Ib Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Phase IIa ApTOLL
Arm Type
Active Comparator
Arm Description
ApTOLL is administered intravenously (two doses selected in Phase Ib). The two dose levels include 35 patients each one.
Arm Title
Phase IIa Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo is administered intravenously in one arm which includes 49 patients.
Intervention Type
Drug
Intervention Name(s)
ApTOLL
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
White freeze-dried powder which is indistinguishable to ApTOLL for taste, color, texture and size.
Primary Outcome Measure Information:
Title
Safety of ApTOLL
Description
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).
Time Frame
From dosing to follow-up (day 90 after dosing)
Secondary Outcome Measure Information:
Title
Mean infarct volume
Description
Magnetic Resonance Image
Time Frame
72 hours
Title
Effect in inflammatory response
Description
Proinflammatory markers in blood between study groups
Time Frame
Predose and up to 72 hours post-dose
Title
Early clinical course
Description
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)
Time Frame
72 hours post-dose
Title
Long-term outcome
Description
mRS (modified Ranking Score). Coded from 0 (no symptoms at all) through 5 (severe disability) 6 (death).
Time Frame
Day 90 post-dose

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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). 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. Exclusion Criteria: 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. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Ribó, MD, PhD
Organizational Affiliation
aptaTargets S.L.
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Macarena Hernández, PhD
Organizational Affiliation
aptaTargets S.L.
Official's Role
Study Director
Facility Information:
Facility Name
Centre Hospitalier Régional Universitaire de Lille
City
Lille
Country
France
Facility Name
Foundation Adolphe de Rothschild
City
Paris
Country
France
Facility Name
Centre Hospitalier Universitaire de Toulouse
City
Toulouse
Country
France
Facility Name
Universitätsklinikum Essen
City
Essen
Country
Germany
Facility Name
Hospital Universitario Central de Asturias
City
Asturias
Country
Spain
Facility Name
Hospital Bellvitge
City
Barcelona
Country
Spain
Facility Name
Hospital Germans Trias i Pujol
City
Barcelona
Country
Spain
Facility Name
Hospital Universitario Vall d´Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital Universitario A Coruña
City
Coruña
Country
Spain
Facility Name
Hospital Universitario de Gerona Dr. Josep Trueta
City
Gerona
Country
Spain
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
Country
Spain
Facility Name
Hospital Universitario La Princesa
City
Madrid
Country
Spain
Facility Name
Hospital Universitario Ramón y Cajal
City
Madrid
Country
Spain
Facility Name
Hospital Virgen del Rocío
City
Sevilla
Country
Spain
Facility Name
Hospital Universitario y Politécnico La Fe
City
Valencia
Country
Spain
Facility Name
Hospital Clínico Valladolid
City
Valladolid
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
All results obtained in this study will be published.
Citations:
PubMed Identifier
35402075
Citation
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.
Results Reference
background
PubMed Identifier
34174279
Citation
Duran-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.
Results Reference
derived
Links:
URL
http://aptatargets.com
Description
Biotechnology company specialized in therapeutic aptamers

Learn more about this trial

Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke

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