Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

Thrombolysis in Mild Stroke: A Comparative Analysis of the PRISMS and MaRISS Studies.

Background and Purpose: Mild ischemic stroke patients enrolled in randomized controlled trials of thrombolysis may have a different symptom severity distribution than those treated in routine clinical practice. Methods: We compared the distribution of the National Institutes of Health Stroke Scale (NIHSS) scores, neurological symptoms/severity among patients enrolled in the PRISMS (Potential of r-tPA for Ischemic Strokes With Mild Symptoms) randomized controlled trial to those with NIHSS score ≤5 enrolled in the prospective MaRISS (Mild and Rapidly Improving Stroke Study) registry using global P values from χ2 analyses. Results: Among 1736 participants in MaRISS, 972 (56%) were treated with alteplase and 764 (44%) were not. These participants were compared with 313 patients randomized in PRISMS. The median NIHSS scores were 3 (2­4) in MaRISS alteplase-treated, 1 (1­3) in MaRISS non­alteplase-treated, and 2 (1­3) in PRISMS. The percentage with an NIHSS score of 0 to 2 was 36.3%, 73.3%, and 65.2% in the 3 groups, respectively (P<0.0001). The proportion of patients with a dominant neurological syndrome (≥1 NIHSS item score of ≥2) was higher in MaRISS alteplase-treated (32%) compared with MaRISS nonalteplase-treated (13.8%) and PRISMS (8.6%; P<0.0001). Conclusions: Patients randomized in PRISMS had comparable deficit and syndromic severity to patients not treated with alteplase in the MaRISS registry and lesser severity than patients treated with alteplase in MaRISS. The PRISMS trial cohort is representative of mild patients who do not receive alteplase in current broad clinical practice.

Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial.

Importance: More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. Objective: To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. Design, Setting, and Participants: The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. Interventions: Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). Main Outcomes and Measures: The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. Results: Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, -1.1%; 95% CI, -9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02072226.

Population Pharmacokinetics of Tenecteplase in Patients With Acute Myocardial Infarction and Application to Patients With Acute Ischemic Stroke.

The pharmacokinetics (PK) of tenecteplase in patients with acute ischemic stroke has not been extensively studied. This study aimed to describe PK characteristics of tenecteplase in patients with acute myocardial infarction (AMI) using a population PK approach and to assess applicability of the findings to patients with acute ischemic stroke by means of external validation. A population PK model was developed using nonlinear mixed-effects modeling based on the phase II TIMI 10B study in patients with AMI (785 PK observations from 103 patients). The statistical and clinical impact of selected covariates on PK parameters were evaluated by a stepwise covariate modeling procedure and simulations, respectively. The performance of the final model was evaluated for patients with acute ischemic stroke using summary statistics of tenecteplase concentrations of 75 patients from investigator-initiated study N1811s. Tenecteplase PK was well described by a 2-compartment linear model, incorporating allometric scaling of clearance and volume parameters and weight-normalized creatinine clearance on clearance. Simulations showed that the identified covariates (weight and creatinine clearance) were of limited influence on exposure at the intended dosing regimen for patients with acute ischemic stroke. The model overpredicted mean tenecteplase plasma concentrations from N1811s by 39%, but 72% of the distribution from N1811s was within the 90% prediction interval of the model predictions. The PK characteristics of tenecteplase in patients with AMI were well described by the final model. Simulations from the model indicated that no specific dose recommendations based on covariates are warranted for patients with AMI.

A Phase III, prospective, double-blind, randomized, placebo-controlled trial of thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase (TIMELESS): Rationale and design.

RATIONALE: While thrombolysis is standard of care for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset, the benefit of tenecteplase beyond this time window is less certain. AIM: The TIMELESS trial (NCT03785678) aims to determine if treatment with tenecteplase increases the proportion of good clinical outcomes among patients with stroke due to a large vessel occlusion who present beyond 4.5 h after symptom onset. SAMPLE SIZE ESTIMATES: A total of 456 patients will provide ⩾90% power to detect differences in the distribution of modified Rankin Scale scores at Day 90 at the two-sided 0.049 significance level. METHODS AND DESIGN: TIMELESS is a Phase III, double-blind, randomized, placebo-controlled trial of tenecteplase with or without endovascular thrombectomy in patients with AIS and evidence of salvageable tissue via imaging who present within the 4.5- to 24-h time window with an internal carotid artery (ICA) or middle cerebral artery (MCA) (M1/M2) occlusion. STUDY OUTCOMES: The primary efficacy objective of tenecteplase compared with placebo will be evaluated with ordinal modified Rankin Scale scores at Day 90. Safety will be evaluated via incidence of symptomatic intracranial hemorrhage, incidence and severity of adverse events, and mortality rate. DISCUSSION: Results from TIMELESS will contribute to understanding of the safety and efficacy of tenecteplase administered 4.5-24 h following symptom onset for patients with an ICA or MCA occlusion.

Choosing the Correct "-ase" in Acute Ischemic Stroke: Alteplase, Tenecteplase, and Reteplase.

Alteplase is a tissue plasminogen activator approved for treating acute ischemic stroke (AIS), acute myocardial infarction (AMI), and acute massive pulmonary embolism. Two additional tissue plasminogen activators, tenecteplase and reteplase, are also approved for AMI treatment. However, neither tenecteplase nor reteplase is approved for AIS treatment. The U.S. Food and Drug Administration has received reports of accidental administration of tenecteplase or reteplase instead of alteplase in patients with AIS, which can lead to potential overdose. Primary factors contributing to medication errors include use of the abbreviations "TPA," "tPA," or "TNK" in written or verbal orders and use of these agents in similar settings. Steps to reduce the likelihood of accidental substitution include use of full brand or generic names and inclusion of the indication in written and verbal orders, addition of alerts in automated dispensing machines and ordering systems, and use of stroke boxes containing alteplase and materials for administration.

Making a case for the right '-ase' in acute ischemic stroke: alteplase, tenecteplase, and reteplase.

INTRODUCTION: Alteplase, reteplase, and tenecteplase are tissue plasminogen activators (TPA) approved for the management of acute myocardial infarction. Only alteplase is also approved for the treatment of acute ischemic stroke (AIS). The US Food and Drug Administration has received reports of accidental administration of tenecteplase or reteplase instead of alteplase in patients with AIS, which can result in failure to treat patients with the intended agent and lead to potential overdose. AREAS COVERED: This review compares the molecular and clinical features of alteplase, reteplase, and tenecteplase (TNK), identifies factors contributing to medication errors among these agents, and provides steps to reduce medication errors. EXPERT OPINION: Primary factors contributing to medication errors among tissue plasminogen activators include the use of the abbreviations 'TPA,' 'tPA,' or 'TNK' in written or verbal orders and use of these agents in similar settings (e.g. emergency departments and critical care areas). Steps to reduce the likelihood of accidental substitution of tenecteplase or reteplase for alteplase in patients with AIS include the use of full brand or generic names and inclusion of the indication in written and verbal orders, the addition of alerts in automated dispensing machines and ordering systems and use of stroke boxes containing alteplase and materials for administration.

Alteplase for the treatment of acute ischemic stroke in patients with low National Institutes of Health Stroke Scale and not clearly disabling deficits (Potential of rtPA for Ischemic Strokes with Mild Symptoms PRISMS): Rationale and design.

Rationale Over half of acute ischemic stroke patients have a low National Institutes of Health Stroke Scale of 0-5 and up to two-thirds may not appear clearly disabled at presentation. The efficacy of intravenous alteplase for the latter group is not known. Aim Potential of rtPA for Ischemic Strokes with Mild Symptoms (PRISMS) was designed to evaluate the safety and efficacy of intravenous alteplase for the treatment of acute ischemic stroke with National Institutes of Health Stroke Scale 0-5 and without clearly disabling deficits. Sample size estimates A maximum of 948 subjects were required to test the superiority hypothesis with 80% power, according to a one-sided 0.025 level of significance. Methods and design PRISMS was a multicenter, randomized, double-blind, placebo-controlled phase 3b clinical trial. Patients were randomized to the active arm (intravenous alteplase standard dose of 0.9 mg/kg, up to a maximum of 90 mg, plus oral aspirin placebo) or the control arm (intravenous alteplase placebo plus active oral aspirin dose of 325 mg). Study outcome The primary efficacy endpoint was favorable functional outcome, defined as a modified Rankin Scale score 0 or 1 assessed at 90-day postrandomization.