A Phase III, Randomized, Multi-center Clinical Trial That Will Examine Whether Treatment With Intravenous TNK is Superior to Placebo in Patients Who Suffer a Non-large Vessel Occlusion Ischemic Stroke Within 4.5-12 Hours From Time Last Seen Well
Overview
- Phase
- Phase 3
- Intervention
- Placebo
- Conditions
- Ischemic Stroke, Acute
- Sponsor
- Hospital Moinhos de Vento
- Enrollment
- 466
- Locations
- 14
- Primary Endpoint
- Rates of Good Functional Outcomes adjusted for the baseline mRS and stroke severity (NIHSS) according to the modified Rankin Scale scores at 90 days
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
A phase III, randomized, multi-center clinical trial that will examine whether treatment with intravenous TNK is superior to placebo in patients who suffer a non-large vessel occlusion ischemic stroke within 4.5-12 hours from time last seen well. The randomization employs a 1:1 ratio of intravenous thrombolysis with Tenecteplase (TNK) versus placebo in patients who suffer a non-large vessel occlusion ischemic stroke between 4.5 and 12 hours from time last seen well (TLSW) and with a clinical-radiological mismatch or evidence of salvageable brain tissue on perfusion imaging.
Detailed Description
Prospective, multi-center, randomized, controlled, double blinded trial. The randomization employs a 1:1 ratio of intravenous thrombolysis with Tenecteplase (TNK) versus placebo in patients who suffer a non-large vessel occlusion ischemic stroke between 4.5 and 12 hours from time last seen well (TLSW) and with a clinical-radiological mismatch or evidence of salvageable brain tissue on perfusion imaging. Randomization will be done under a minimization process using age (≤70 vs. \>70 years), baseline NIHSS (≤10 vs. \>10), therapeutic window (4.5-9 or 9-12 hours after TLKW), randomization scenario and clinical site. For the primary endpoint, subjects will be followed for 90 days post-randomization. The total sample size is 466 participants (233 in each arm). Interim analysis is planned with 40% and 67% of the total sample, with the possibility of stopping due to efficacy or futility, in addition to an adaptive design based on the conditional probability of a positive result.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment with Alteplase due to onset \>4.5 hours and is ineligible for endovascular treatment under standard of care due to absence of proximal arterial occlusion (e.g. intracranial ICA, MCA-M1 and dominant M2 segments, and vertebrobasilar arteries).
- •\* Dominant M2 segment is defined is a division supplying \>50% of the MCA territory vs co-dominant supplying 50% of the MCA territory vs non-dominant supplying \<50% of the MCA territory.
- •No significant pre-stroke functional disability (mRS ≤2).
- •Age ≥18 years (no upper age limit).
- •Clinical or imaging mismatch evidence in distal artery territories, defined as one of the following scenarios (A, B or C):
- •Scenario A - all of the following:
- •Significant cortical neurological deficit (moderate to severe afasia, moderate to severe heminegligence, severe hemianopsia) with the addition or not of motor symptoms OR any motor deficit accompanied of cortical symptoms of any severity;
- •Contrast-enhanced CT of the head or head MRI with \<50% involvement of the vascular territory corresponding to the clinical manifestation;
- •Arterial head angiotomography or arterial head angioMRI WITHOUT proximal intracranial artery occlusion that would require endovascular therapy (for example, ICA intracranial, MCA-M1 and M2 dominant segments and vertebral and basilar arteries)
- •Scenario B - all of the following:
Exclusion Criteria
- •Intracranial hemorrhage (ICH) identified by CT or MRI.
- •Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient without eligibility criteria.
- •Pre-stroke mRS score of ≥ 2 (indicating previous disability)
- •Contra indication to imaging with MR or CT with contrast agents.
- •Infarct core \>1/3 MCA territory qualitatively or \>50 mL quantitatively (determined by DWI lesion on MR).
- •Participation in any investigational study in the previous 30 days
- •Any terminal illness such that patient would not be expected to survive more than 1 year).
- •Baseline platelet count \< 100.000/µL
- •Woman of childbearing potential who is known to be pregnant or who has a positive pregnancy test on admission.
- •Previous stroke within last three months.
Arms & Interventions
Control group
Placebo administered as a single bolus injection over 5 seconds
Intervention: Placebo
Intravenous tenecteplase (TNK)
Intravenous thrombolysis with Tenecteplase (TNK) at a dose of 0.25 mg/Kg (maximum 25mg, administered as a bolus over 5 seconds)
Intervention: Intravenous tenecteplase
Outcomes
Primary Outcomes
Rates of Good Functional Outcomes adjusted for the baseline mRS and stroke severity (NIHSS) according to the modified Rankin Scale scores at 90 days
Time Frame: 90 days
Rates of Good Functional Outcomes adjusted for the baseline mRS and stroke severity (NIHSS) according to the modified Rankin Scale scores at 90 days as following: Baseline mRS=0 and NIHSS \<10: mRs 90 days ≤1 Baseline mRS=1 and NIHSS ≥10: mRs 90 days ≤2
Secondary Outcomes
- Rates of Excellent Outcome defined as mRS ≤ 1 and/ or equal to Baseline mRS at 90 days(90 days)
- Rates of Independent Outcome defined as mRS ≤ 2 and/ or equal to Baseline mRS at 90 days(90 days)
- Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS) at 90 days(90 days)
- Final infarct volume (FIV) and infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 24 hours (-2/+12 hours)(24 hours (-2/+12 hours))
- Clinically significant ICH rates at 24 (-2/+12) hours.(24 (-2/+12) hours)
- Incidence of any intracranial hemorrhage (Heidelberg criteria) measured at 24 (-2/+12)(24 (-2/+12))
- Final infarct volume (FIV) and infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 3-5 days (if available)(3-5 days)
- Mortality at 90 days ( safety outcome)(90 days)
- Dramatic early favorable response as determined by an NIHSS of 0-2 or NIHSS improvement ≥ 4 points at 24 (-2/+12 hours) hours(24 (-2/+12 hours) hours)
- Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year, between interventional therapy vs medical therapy alone(3 month, 6 months and one year)
- Brain tissue reperfusion evaluated by CT or MRI perfusion at 24 hours in both treatment groups (if available)(24 hours)
- Distribution of the modified Rankin Scale scores at 90 days (shift analysis) as evaluated by two separate assessors at the central core lab) who are blinded to treatment.(90 days)