Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2)

Ischemic Stroke Clinical Trial

Official title:

EXTEND-IA TNK: Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial Using Intravenous Tenecteplase Part 2

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03340493
• Other study ID #: NTA1401a
• Status: Completed
• Phase: Phase 2
• Start date: December 6, 2017
• Est. completion date: February 1, 2020

Study information

• Verified date: March 2020
• Source: Neuroscience Trials Australia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients presenting to the emergency department with acute ischemic stroke, who are eligible for standard intravenous thrombolysis within 4.5 hours of stroke onset will be assessed for major vessel occlusion to determine their eligibility for randomization into the trial. If the patient gives informed consent they will be randomised 50:50 using central computerised allocation to either 0.4mg/kg or 0.25mg/kg intravenous tenecteplase before all participants undergo endovascular thrombectomy. The trial is prospective, randomised, open-label, blinded endpoint (PROBE) design.

Description:

The study will be a multicentre, prospective, randomized, open- label, blinded endpoint (PROBE), controlled phase 2 trial (2 arm with 1:1 randomization) in ischemic stroke patients.

Randomized patients will first be stratified by both the setting of treatment: metropolitan hospital vs regional hospital (>1 hour transfer to endovascular centre) vs mobile stroke unit; and by site of baseline arterial occlusion: Intracranial internal carotid artery (ICA) and Basilar artery versus Middle cerebral artery (MCA - M1 and M2); overall resulting in six strata.

Imaging is performed with CT or MR (magnetic resonance) acutely as part of standard care with imaging follow-up at 18-30 hours. The sequences and the parameters used follow the STIR (Stroke Imaging Research) roadmap guidelines, but imaging takes place acutely and at 18- 30hrs only, as previously validated.

The sample size estimation was based on the proportion of pre-endovascular reperfusion observed in the 0.25mg/kg group from Part 1 of EXTEND-IA TNK (22%). An estimated total sample size of 188 patients (with 94 patients in each of treatment and control arms) yielded 80% power to detect a significant difference of 20% in strata-weighted angiographic reperfusion (mTICI 2b/3) at initial angiogram (22% in 0.25mg/kg vs 42% in 0.4mg/kg arm) at two-sided statistical significance threshold of p=0.05 for superiority. Adaptive increase in sample size will be performed if the result of interim analysis using data from the first 150 patients is promising, as per the methodology of Mehta and Pocock.

During the trial, blinded analysis of operational characteristics revealed a 20% reduction in the time from thrombolysis to arterial access versus part 1 due to improved workflow (In the first 150 patients in part 2 median 37min [IQR 19-54] versus 46min [IQR 28-63] in part 1). This directly impacts the time for thrombolysis to have an effect. A 20% reduction in the hypothesized rate of reperfusion at initial angiogram (18% vs 33%) would require 145 patients per group. Allowing for potential further improvements in workflow the sample size re-estimation was postponed from 150 to 240 patients with a revised minimum sample of 300 patients. Adaptive increase in sample size will be performed if the result of interim analysis using data from the first 240 patients is promising, as per the methodology of Mehta and Pocock. The maximum sample size is capped at 656 patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: February 1, 2020
• Est. primary completion date: July 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients presenting with acute ischemic stroke eligible using standard criteria to receive IV thrombolysis within 4.5 hours of stroke onset

• Patient's age is =18 years

• Arterial occlusion on CTA (computed tomography angiography) or MRA (Magnetic Resonance Angiography) of the ICA, M1, M2 or basilar artery.

Exclusion Criteria:

• Intracranial hemorrhage (ICH) identified by CT or MRI

• Rapidly improving symptoms at the discretion of the investigator

• Pre-stroke mRS score of = 4 (indicating previous disability)

• Hypodensity in >1/3 MCA territory or equivalent proportion of basilar artery territory on non-contrast CT

• Contra indication to imaging with contrast agents

• Any terminal illness such that patient would not be expected to survive more than 1 year

• Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study.

• Pregnant women

Related Conditions & MeSH terms

• Ischemia
• Ischemic Stroke
• Stroke

Intervention

Drug:
• Tenecteplase
Tenecteplase 0.25mg/kg and 0.4mg/kg are being used

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Albury Hospital	Albury	New South Wales
Australia	Ballarat Health Services	Ballarat	Victoria
Australia	Bankstown-Lidcombe Hospital	Bankstown	New South Wales
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Royal Brisbane & Women's Hospital	Brisbane	Queensland
Australia	Campbelltown Hospital	Campbelltown	New South Wales
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	Gold Coast University Hospital	Gold Coast	Queensland
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	Sunshine Coast University Hospital	Nambour	Queensland
Australia	John Hunter Hospital	Newcastle	New South Wales
Australia	Goulburn Valley Health	Shepparton	Victoria
Australia	Western Heath	St Albans	Victoria
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Latrobe Regional Hospital	Traralgon	Victoria
Australia	North East Health Wangaratta	Wangaratta	Victoria
Australia	South West Healthcare	Warrnambool	Victoria
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Auckland Hospital	Grafton	Auckland

Sponsors (2)

Lead Sponsor	Collaborator
Neuroscience Trials Australia	The Florey Institute of Neuroscience and Mental Health

Countries where clinical trial is conducted

Australia,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	mTICI	Proportion of patients with substantial angiographic reperfusion (mTICI) score of 2b/3 (restoration of blood flow to >50% of the affected arterial territory) or absence of retrievable thrombus at initial angiogram.	Initial angiogram (day 0)
Secondary	Modified Rankin Scale (mRS)	mRS ordinal analysis. mRS 0-1 or no change from baseline and mRS 0-2 or no change from baseline.	at 3 months post stroke
Secondary	National Institutes of Health Stroke Scale (NIHSS)	Proportion of patients with =8 point reduction in NIHSS or reaching 0-1 at 3 days (favourable clinical response) adjusted for baseline NIHSS and age	Initial angiogram (day 0)
Secondary	Symptomatic intracranial haemorrhage (SICH)	SICH is defined as "Intracerebral hemorrhage (parenchymal hematoma type 2 - PH2 within 36 hours of treatment) combined with neurological deterioration leading to an increase of =4 points on the NIHSS"	Within 36 hours post treatment
Secondary	Death	Death due to any cause	Up to 3 months post stroke
Secondary	Angiographic reperfusion	Proportion of patients with angiographic reperfusion adjusted for hyperdense clot length on non-contrast CT and time from thrombolysis to initial angiogram	Up to 24 hours post treatment