Clinical trial NCT04734548: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Stroke
Acute Stroke
Ischemic Stroke
Lead sponsor: aptaTargets S.L.
Sponsor class: INDUSTRY
Collaborators: name: Ministry of Science and Innovation, Spain
name: Anagram
First posted: 2021-02-02
Enrollment: 151
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety of ApTOLL
timeFrame: From dosing to follow-up (day 90 after dosing)
Secondary outcomes:
measure: Mean infarct volume
timeFrame: 72 hours
measure: Effect in inflammatory response
timeFrame: Predose and up to 72 hours post-dose
measure: Early clinical course
timeFrame: 72 hours post-dose
measure: Long-term outcome
timeFrame: Day 90 post-dose
Other outcomes:
Locations:
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille
city: Paris
country: France
facility: Foundation Adolphe de Rothschild
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Asturias
country: Spain
facility: Hospital Universitario Central de Asturias
city: Barcelona
country: Spain
facility: Hospital Bellvitge
city: Barcelona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebron
city: Coruña
country: Spain
facility: Hospital Universitario A Coruña
city: Gerona
country: Spain
facility: Hospital Universitario de Gerona Dr. Josep Trueta
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Valladolid
country: Spain
facility: Hospital Clínico Valladolid
Study officials:
affiliation: aptaTargets S.L.
name: Marc Ribó, MD, PhD
role: STUDY_DIRECTOR
affiliation: aptaTargets S.L.
name: Macarena Hernández, PhD
role: STUDY_DIRECTOR
References:
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.
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.