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Combinating Fingolimod With Alteplase Bridging With Mechanical Thrombectomy in Acute Ischemic Stroke (FAMTAIS)

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ClinicalTrials.gov Identifier: NCT02956200
Recruitment Status : Unknown
Verified September 2016 by Second Affiliated Hospital, School of Medicine, Zhejiang University.
Recruitment status was:  Not yet recruiting
First Posted : November 7, 2016
Last Update Posted : November 8, 2016
Sponsor:
Information provided by (Responsible Party):
Second Affiliated Hospital, School of Medicine, Zhejiang University

Brief 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.

Condition or disease Intervention/treatment Phase
Stroke Inflammation Drug: Fingolimod Phase 2

Detailed 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomised Controlled Trial of Combinating an Immune Modulator Fingolimod With Alteplase Bridging With Mechanical Thrombectomy in Acute Ischemic Stroke
Study Start Date : November 2016
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


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 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.
Other Name: Fingolimod Hydrochloride

No Intervention: standard therapy
Patients will be treated with standard alteplase bridging and mechanical thrombectomy.



Primary Outcome Measures :
  1. salvaged ischemic tissue index (%) [ Time Frame: from baseline to 7 day ]
    100*(baseline CTP ischemic lesion (mL) - 7 day DWI infarction lesion (mL))/ baseline CTP ischemic lesion (mL)


Secondary Outcome Measures :
  1. the growth in infarct volume (mL) [ Time Frame: from 24 hour to 7 day ]
    24 hour DWI infarct volume (mL) - 7 day FLAIR infarct volume (mL)

  2. the penumbral salvage volume (mL) [ Time Frame: from baseline to 1 day ]
    (baseline CTP hypoperfusion volume (mL) - 24 hour DWI infarct volume (mL))

  3. the frequency of parenchymal hemorrhage (PH) (%) [ Time Frame: at day 1 ]
    the presence of PH is defined according the standard from ECASS-2 study

  4. the change on the NIHSS score [ Time Frame: from baseline to 1 day ]
    baseline NIHSS score - 1 day NIHSS score

  5. the change on the NIHSS score [ Time Frame: from baseline to 7 day ]
    baseline NIHSS score - 7 day NIHSS score

  6. excellent recovery [ Time Frame: at day 90 ]
    modefied Rankin Scale (mRS) score of 0-1

  7. independent recovery [ Time Frame: at day 90 ]
    mRS score of 0-2



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02956200


Contacts
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Contact: Min Lou, MD,PhD loumingxc@vip.sina.com

Locations
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China, Zhejiang
The second affiliated hospital of Zhejiang University
Hangzhou, Zhejiang, China, 310000
Sponsors and Collaborators
Second Affiliated Hospital, School of Medicine, Zhejiang University
Investigators
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Study Chair: Min Lou, MD,PhD Second Affiliated Hospital of Zhejiang University, School of Medicine

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Responsible Party: Second Affiliated Hospital, School of Medicine, Zhejiang University
ClinicalTrials.gov Identifier: NCT02956200     History of Changes
Other Study ID Numbers: YAN-2016-047
First Posted: November 7, 2016    Key Record Dates
Last Update Posted: November 8, 2016
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Second Affiliated Hospital, School of Medicine, Zhejiang University:
Fingolimod Hydrochloride
Intravenous thrombolysis
Mechanical thrombectomy
Acute ischemic stroke

Additional relevant MeSH terms:
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Stroke
Inflammation
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Tissue Plasminogen Activator
Fingolimod Hydrochloride
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action