Intra-arterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS EXP)

Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke

SYNTHESIS is a pragmatic multicenter randomized controlled trial (RCT), open-label, with blinded follow-up aiming to determine whether loco-regional intra-arterial (IA) with recombinant tissue-plasminogen activator (rt-PA) and/or mechanical devices, as compared with systemic intravenous (I.V.) infusion of rt-PA within 3 hours of ischemic stroke, increases the proportion of independent survivors at 3 months.

Study Overview

• Status: Completed
• Conditions: Stroke; Cerebrovascular Accident
• Intervention / Treatment: Other: Alteplase IA and/or mechanical thrombolysis; Drug: Alteplase IV

Detailed Description

Eligibility criteria:patients with symptomatic, CT verified, acute ischemic stroke, being able to initiate IV rt-PA within 3 hours and IA thrombolysis within 6 hours of stroke onset, when uncertainty about appropriateness the two approaches exists as established by the treating physician.

Eligible patients are randomized to receive either 0.9 mg/kg (max 90 mg) IV rt-PA (control arm) or up to 0.9 mg/Kg IA rt-PA (max 90 mg) over 60 minutes into the thrombus, eventually associated with clot mechanical disaggregation/dislocation or retraction/aspiration. Mechanical thrombolysis is possible also without the use of rt-PA. The procedural choices of the interventional neuroradiologist depend on the type of occlusion, circumstances and experience.

The study is designed to detect or disprove (alpha=5% and power probability=80%) a 15% absolute difference between the treatment groups in the percentage of patients with a favourable outcome (Modified Rankin Scale Score = 0-1).Enrollment will be completed with 350 randomized patients.

Neurological deficit will be scored with NIH Stroke Scale at day 7 or discharge, or transfer to another hospital, whichever occurs first.Patient's clinical condition will be again evaluated by a telephone call after 90 days.

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20162
    • A.O. Ospedale Ca' Granda

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Sudden focal neurological deficit attributable to a stroke
• Clearly defined time of onset, allowing initiation of intravenous treatment within 3 hours of symptoms onset and intra-arterial treatment within 6 hour of symptoms onset.
• Age greater than 18 years

Exclusion Criteria:

• Disability preceding stroke consistent with a modified Rankin scale score of 2-4
• Coma at onset
• Rapidly improving neurological deficit
• Seizure at onset
• Clinical presentation suggestive of a subarachnoid hemorrhage
• Previous history of intracranial hemorrhage
• Septic embolism
• Arterial puncture at a non compressible site within the previous 7 days
• Any traumatic brain injury within the previous 14 days
• Surgery of the central nervous system in the previous 3 months
• Gastrointestinal hemorrhage or urinary tract hemorrhage within the previous 14 days.
• Current therapy with intravenous or subcutaneous heparin to rise the clotting time
• Known hereditary or acquired hemorrhagic diathesis, baseline INR greater than 1.5, aPTT more than 1.5 times normal, or baseline platelet count less than 100,000 per cubic millimeter
• Baseline blood glucose concentrations below 2.75 mm/L (50 mg/dL).
• Known contrast sensitivity.
• Women of childbearing potential (unless pregnancy impossible) or known to be breastfeeding. Uncontrolled hypertension defined by a blood pressure greater or equal 185 mmHg systolic or diastolic greater or equal 110 mm Hg in 3 separate occasions at least 10 minutes apart or requiring continuous IV therapy.
• Prognosis very poor regardless of therapy; likely to be dead within months.
• Unlikely to be available for follow-up (eg, no fixed home address, visitor from overseas).
• Any other condition which local investigators feels would pose a significant hazard in terms of risk/benefit to the patient, or if therapies are impracticable.

COMPUTED TOMOGRAPHIC (CT) SCAN EXCLUSION CRITERIA

• Intracranial tumors except small meningioma
• Hemorrhage of any degree
• Acute infarction (since this may be an indicator that the time of onset is uncorrected)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IA thrombolysis; IA recombinant tissue plasminogen activator and/or mechanical thrombolysis	Other: Alteplase IA and/or mechanical thrombolysis; loca intra-arterial recombinant tissue plasminogen activator and/or mechanical thrombolysis
Active Comparator: IV rtPA; IV recombinant tissue plasminogen activator	Drug: Alteplase IV; intravenous recombinant tissue plasminogen activator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To assess whether IA thrombolysis, as compared to IV rt-PA, increases survival free of disability (modified Rankin score of zero or 1) at 3 months.	3 months

Secondary Outcome Measures

Outcome Measure	Time Frame
To asses whether IA thrombolysis vs.IV rt-PA 1.improves the 7 day neurological deficit; 2.is safe on the base of symptomatic intracranial hemorrhages, fatal and non-fatal stroke, death from any cause, neurological deterioration within 7 days	7 days

Collaborators and Investigators

• Sponsor: Niguarda Hospital
• Investigators: Principal Investigator: Alfonso Ciccone, MD, A.O. Ospedale Niguarda Ca' Granda

Publications and helpful links

General Publications

• Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, Boccardi E; SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):904-13. doi: 10.1056/NEJMoa1213701. Epub 2013 Feb 6.

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: March 18, 2008
• First Submitted That Met QC Criteria: March 18, 2008
• First Posted (Estimate): March 21, 2008

Study Record Updates

• Last Update Posted (Estimate): April 25, 2014
• Last Update Submitted That Met QC Criteria: April 24, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: thrombolysis; Acute ischemic stroke; intra-arterial thrombolysis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator
• Other Study ID Numbers: SYNTHESIS EXPANSION