Combinating Fingolimod With Alteplase Bridging With Thrombectomy in Acute Ischemic Stroke

A Randomised Controlled Trial of Combinating an Immune Modulator Fingolimod With Alteplase Bridging With Mechanical Thrombectomy in Acute Ischemic Stroke

Proof-of concept clinical trials have indicated that the sphingosine-1-phosphate receptor modulator fingolimod may be efficacious in attenuating brain inflammation and improving clinical outcomes in patients with AIS as a single therapy beyond 4.5 hours of disease onset, or in combination with alteplase within 4.5 hours of disease onset. So in this study the investigators try to determine whether the addition of fingolimod, administered within 24 hours after the onset of symptoms in patients receiving alteplase bridging with mechanical thrombectomy, improves radiologic and clinical outcomes.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Inflammation
• Intervention / Treatment: Drug: Fingolimod; Other: Placebo

Detailed Description

This is a prospective, randomized, double-blind, placebo-controlled design clinical trial, in multiple stroke centers of China. The total sample size will be 118. Patients being treated with standard alteplase bridging and mechanical thrombectomy will be randomly assigned in a 1:1 ratio to receive fingolimod or placebo.

Patients aged between 18 and 85 with anterior circulation AIS who are eligible for alteplase and mechanical thrombectomy commenced within 24 hours of stroke onset or awakening with stroke (if within 24 hours from the midpoint of sleep) will be enrolled if they present with an infarct core volume ≤ 100 mL and penumbra ≥ 15 mL with at least 20% mismatch (as evaluated by CTP) and intracranial occlusion in proximal cerebral arteries. Exclusion criteria are (1) pre-existing neurologic disability (a score greater than 2 on the mRS); (2) contraindication of fingolimod.

As standard care, all patients will receive standard dose intravenous alteplase (0.9 mg per kilogram, the first 10% administered as an initial bolus and the remainder over a 1-hour period, with a maximum dose of 90 mg) and mechanical thrombectomy delivered at the site of intracranial vessel occlusion. Patients randomized to fingolimod group or placebo group will receive fingolimod (Gilenya, Novartis) at a dosage of 0.5 mg or placebo once daily, for three consecutive days, with the first dose being given at the time in which patients are enrolled which is about one hour prior to mechanical thrombectomy.

The kinetics of lymphocyte subset alteration will be monitored in whole-blood samples from all fingolimod- treated patients at the baseline, which will precede the first dose, day 1 and day 7. Mononuclear cells will be isolated from the whole-blood specimens and stained with antibodies to CD4-FITC, CD8-PE, CD19-PerCP, CD56-PE (BD Biosciences, Franklin Lakes, NJ, USA). Data will be acquired using a FACS Caliber (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA) and analyzed with Flow Jo software (Tree Star, Ashland, OR, USA).

The primary outcome is the ratio of mRS 0-2 (%) at 90 day. Secondary outcomes are the salvaged ischemic tissue index (%) from baseline to 7 day, the growth in infarct volume (mL) from 24 hour to 7 day, the penumbral salvage volume (mL) from baseline to 1 day, the frequency of parenchymal hemorrhage (PH) (%) at day 1, the change on the NIHSS score from baseline to 1 day, the change on the NIHSS score from baseline to 7 day, mRS 0-1 (%) at 90 day, and mRS at 90 day.

• Study Type: Interventional
• Enrollment (Anticipated): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • Recruiting
      • The Second Affiliated Hospital of Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients presenting with anterior circulation acute ischaemic stroke who are eligible for alteplase and mechanical thrombectomy commenced within 24 hours of stroke onset or awakening with stroke (if within 24 hours from the midpoint of sleep).
• Patient's age is 18-85 years.
• Arterial occlusion on CTA of the ICA, M1 or M2.
• Imaging inclusion criteria: infarct core volume ≤ 100 mL and penumbra ≥ 15 mL with at least 20% mismatch (as evaluated by CTP).
• Patient, family member or legally responsible person depending on local ethics requirements has given informed consent.

Exclusion Criteria:

• Pre-existing neurologic disability (a score greater than 2 on the mRS).
• Contraindication of fingolimod.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: fingolimod with standard therapy; Patients will be treated with standard alteplase bridging and mechanical thrombectomy with fingolimod.	Drug: Fingolimod; Patients randomized to fingolimod will also receive fingolimod (Gilenya, Novartis) at a dosage of 0.5 mg once daily, for three consecutive days, with the first dose being given at the time in which patients are enrolled which is about one hour prior to mechanical thrombectomy.
Placebo Comparator: Placebo with standard therapy; Patients will be treated with standard alteplase bridging and mechanical thrombectomy with placebo.	Other: Placebo; Patients randomized to fingolimod will also receive placebo once daily, for three consecutive days, with the first dose being given at the time in which patients are enrolled which is about one hour prior to mechanical thrombectomy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
independent recovery assessed by ratio of modefied Rankin Scale (mRS) score of 0-2 (%)	mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome	at 90 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the frequency of parenchymal hemorrhage (PH) (%)	the presence of PH is defined according the standard from ECASS-2 study	at day 1
the change on the National Institute of Health stroke scale (NIHSS) score from baseline to 1 day	NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms	from baseline to 1 day
the change on the National Institute of Health stroke scale (NIHSS) score from baseline to 7 day	NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms	from baseline to 7 day
general recovery assessed by the ratio of modefied Rankin Scale (mRS) score of 0-3 (%)	mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome	at day 90
recovery assessed by modefied Rankin Scale (mRS) score	mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome	at day 90
salvaged ischemic tissue index (%)	100*(baseline CTP ischemic lesion (mL) - 7 day DWI infarction lesion (mL))/ baseline CTP ischemic lesion (mL)	from baseline to 7 day
the growth in infarct volume (mL)	24 hour DWI infarct volume (mL) - 7 day DWI infarct volume (mL)	from 24 hour to 7 day
the penumbral salvage volume (mL)	(baseline CTP hypoperfusion volume (mL) - 24 hour DWI infarct volume (mL))	from baseline to 1 day
excellent recovery assessed by the ratio of modefied Rankin Scale (mRS) score of 0-1 (%)	mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome	at day 90

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Collaborators: Shaoxing People's Hospital; Huizhou Municipal Central Hospital; Taizhou Hospital; The Second Affiliated Hospital of Jiaxing University; Jinhua Center Hospital; Affiliated Hospital of Jiaxing University

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2021
• Primary Completion (Anticipated): December 15, 2025
• Study Completion (Anticipated): March 15, 2026

Study Registration Dates

• First Submitted: December 16, 2020
• First Submitted That Met QC Criteria: December 16, 2020
• First Posted (Actual): December 19, 2020

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 16, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Acute ischemic stroke; Mechanical thrombectomy; Intravenous thrombolysis; Fingolimod Hydrochloride
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Inflammation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Fingolimod Hydrochloride
• Other Study ID Numbers: IMMUTAS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No