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

Stroke Clinical Trial

Official title:

A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04734548
• Other study ID #: APRIL
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: October 28, 2020
• Est. completion date: September 7, 2022

Study information

• Verified date: October 2022
• Source: aptaTargets S.L.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 151
• Est. completion date: September 7, 2022
• Est. primary completion date: July 25, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Stroke
• Cerebral Infarction
• Ischemia
• Ischemic Stroke
• Stroke

Intervention

Drug:
• ApTOLL
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.

Other:
• Placebo
White freeze-dried powder which is indistinguishable to ApTOLL for taste, color, texture and size.

Locations

Country	Name	City	State
France	Centre Hospitalier Régional Universitaire de Lille	Lille
France	Foundation Adolphe de Rothschild	Paris
France	Centre Hospitalier Universitaire de Toulouse	Toulouse
Germany	Universitätsklinikum Essen	Essen
Spain	Hospital Universitario Central de Asturias	Asturias
Spain	Hospital Bellvitge	Barcelona
Spain	Hospital Germans Trias i Pujol	Barcelona
Spain	Hospital Universitario Vall d´Hebron	Barcelona
Spain	Hospital Universitario A Coruña	Coruña
Spain	Hospital Universitario de Gerona Dr. Josep Trueta	Gerona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Princesa	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Virgen del Rocío	Sevilla
Spain	Hospital Universitario y Politécnico La Fe	Valencia
Spain	Hospital Clínico Valladolid	Valladolid

Sponsors (3)

Lead Sponsor	Collaborator
aptaTargets S.L.	Anagram, Science and Innovation Spanish Ministry

Countries where clinical trial is conducted

France,  Germany,  Spain, 

References & Publications (1)

Hernández-Jiménez M, Martín-Vílchez S, Ochoa D, Mejía-Abril G, Román M, Camargo-Mamani P, Luquero-Bueno S, Jilma B, Moro MA, Fernández G, Piñeiro D, Ribó M, González 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	From dosing to follow-up (day 90 after dosing)
Secondary	Mean infarct volume	Magnetic Resonance Image	72 hours
Secondary	Effect in inflammatory response	Proinflammatory markers in blood between study groups	Predose and up to 72 hours post-dose
Secondary	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)	72 hours post-dose
Secondary	Long-term outcome	mRS (modified Ranking Score). Coded from 0 (no symptoms at all) through 5 (severe disability) 6 (death).	Day 90 post-dose

External Links

•   Biotechnology company specialized in therapeutic aptamers