Clinical trial NCT02956200: Combinating Fingolimod With Alteplase Bridging With Mechanical Thrombectomy in Acute Ischemic Stroke
Official title: A Randomised Controlled Trial of Combinating an Immune Modulator Fingolimod With Alteplase Bridging With Mechanical Thrombectomy in Acute Ischemic Stroke
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Stroke
Inflammation
Keywords: Fingolimod Hydrochloride
Intravenous thrombolysis
Mechanical thrombectomy
Acute ischemic stroke
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
Collaborators: name: Shaoxing People's Hospital
name: Affiliated Hospital of Jiaxing University
name: Huzhou Center Hospital
name: The Second Affiliated Hospital of Jiaxing University
name: Jinhua Center Hospital
name: Taizhou Hospital
First posted: 2016-11-06
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: salvaged ischemic tissue index (%)
timeFrame: from baseline to 7 day
Secondary outcomes:
measure: the growth in infarct volume (mL)
timeFrame: from 24 hour to 7 day
measure: the penumbral salvage volume (mL)
timeFrame: from baseline to 1 day
measure: the frequency of parenchymal hemorrhage (PH) (%)
timeFrame: at day 1
measure: the change on the NIHSS score
timeFrame: from baseline to 1 day
measure: the change on the NIHSS score
timeFrame: from baseline to 7 day
measure: excellent recovery
timeFrame: at day 90
measure: independent recovery
timeFrame: at day 90
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: The second affiliated hospital of Zhejiang University
state: Zhejiang
Study officials:
affiliation: Second Affiliated Hospital of Zhejiang University, School of Medicine
name: Min Lou, MD,PhD
role: STUDY_CHAIR
References: