Combinating Fingolimod With Alteplase Bridging With Mechanical Thrombectomy in Acute Ischemic Stroke

Stroke Clinical Trial

— FAMTAIS  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02956200
• Other study ID #: YAN-2016-047
• Status: Withdrawn
• Phase: Phase 2
• Start date: November 2016
• Est. completion date: December 2018

Study information

• Verified date: September 2016
• Source: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 6 hours after the onset of symptoms in patients receiving alteplase bridging with mechanical thrombectomy, improves radiologic and clinical outcomes.

Description:

This is a prospective, randomized, open-label, blinded endpoint (PROBE) design clinical trial, in multiple stroke centers of China. The total sample size will be 98. Patients being treated with standard alteplase bridging and mechanical thrombectomy will be randomly assigned in a 1:1 ratio to receive oral fingolimod or standard care. The primary outcome will be the salvaged ischemic tissue from baseline to day 7. AIS patients with proximal cerebral arterial occlusions will have CT perfusion (CTP) before treatment, and multimodal MRI including diffusion and MR perfusion (MRP) at 24 hours and 7 days after receiving treatment. Clinical outcomes will be assessed using the National Institutes of Health Stroke Scale score (NIHSS) at baseline, day 1 and day 7 and the modified Rankin Scale (mRS) at 90 days. Circulating lymphocyte counts will be monitored with FACS at baseline, day 1 and day 7 to confirm the biological activity of fingolimod.

Patients aged between 18 and 85 with anterior circulation AIS who are eligible for alteplase and mechanical thrombectomy commenced within 6 hours of stroke onset will be enrolled if they present with an infarct core volume between 15-100 mL with at least 20% mismatch (as evaluated by CTP) and intracranial occlusion in proximal cerebral arteries. Exclusion criteria are (1) standard contraindications to alteplase or mechanical thrombectomy; (2) evidence of other diseases of the CNS; (3) pre-existing neurologic disability (a score greater than 2 on the mRS); (4) swallowing difficulties that would prevent administration of oral fingolimod; (5) patients with any history of bradyarrhythmia, atrioventricular block or current use of beta-blockers or verapamil; (6) concomitant use of antineoplastic, immunosuppressive or immune modulating therapies; (7) macular edema.

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 will also receive oral 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.

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 salvaged ischemic tissue((baseline ischemic lesion - 7d infarction lesion)/ baseline ischemic lesion) from baseline to day 7. Secondary outcomes are the growth in infarct volume between 24 hour DWI and day 7 FLAIR imaging, the penumbral salvage volume (baseline hypoperfusion volume - 24-hours infarct volume) between the baseline and day 1, the frequency of parenchymal hemorrhage (PH) at day 1 and the extent of clinical improvement at day 1 as measured by the change on the NIHSS score from baseline to day 1, the extent of clinical improvement from day 1 to day 7. The tertiary outcomes are the probability of excellent recovery at day 90 (mRS 0-1), independent recovery (mRS 0-2) and ordinal analysis of the modified Rankin scale.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2018
• Est. primary completion date: October 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

1. Patients presenting with anterior circulation acute ischaemic stroke who are eligible for alteplase and mechanical thrombectomy commenced within 6 hours of stroke onset.

2. Patient, family member or legally responsible person depending on local ethics requirements has given informed consent.

3. Patient"s age is 18-85 years.

4. Arterial occlusion on CTA of the ICA, M1 or M2.

5. Imaging inclusion criteria: infarct core volume between 15-100 mL with at least 20% mismatch (as evaluated by CTP).

Exclusion Criteria:

1. Standard contraindications to alteplase or mechanical thrombectomy.

2. Evidence of other diseases of the CNS.

3. Pre-existing neurologic disability (a score greater than 2 on the mRS).

4. Swallowing difficulties that would prevent administration of oral fingolimod.

5. Patients with any history of bradyarrhythmia, atrioventricular block or current use of beta-blockers or verapamil.

6. Patients with serious acute or chronic infection, or hepatic injury (over 3 times value of normal ALS or AST).

7. Concomitant use of antineoplastic, immunosuppressive or immune modulating therapies.

8. Macular edema.

Related Conditions & MeSH terms

• Inflammation
• Stroke

Intervention

Drug:
• Fingolimod
Patients randomized to fingolimod will also receive oral 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.

Locations

Country	Name	City	State
China	The second affiliated hospital of Zhejiang University	Hangzhou	Zhejiang

Sponsors (7)

Lead Sponsor	Collaborator
Second Affiliated Hospital, School of Medicine, Zhejiang University	Huzhou Center Hospital, Jiaxing People's Hospital, Jiaxing Second Hospital, Jinhua Center Hospital, Shaoxing People's Hospital, Taizhou Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Secondary	the growth in infarct volume (mL)	24 hour DWI infarct volume (mL) - 7 day FLAIR infarct volume (mL)	from 24 hour to 7 day
Secondary	the penumbral salvage volume (mL)	(baseline CTP hypoperfusion volume (mL) - 24 hour DWI infarct volume (mL))	from baseline to 1 day
Secondary	the frequency of parenchymal hemorrhage (PH) (%)	the presence of PH is defined according the standard from ECASS-2 study	at day 1
Secondary	the change on the NIHSS score	baseline NIHSS score - 1 day NIHSS score	from baseline to 1 day
Secondary	the change on the NIHSS score	baseline NIHSS score - 7 day NIHSS score	from baseline to 7 day
Secondary	excellent recovery	modefied Rankin Scale (mRS) score of 0-1	at day 90
Secondary	independent recovery	mRS score of 0-2	at day 90