Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection.

BACKGROUND AND PURPOSE: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. METHODS: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. RESULTS: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. CONCLUSIONS: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.

Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.

BACKGROUND: TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III. PURPOSE: (1) To review the trial design and comprehensive type I error rate simulations and (2) to discuss issues raised during regulatory review, to facilitate future approval of similar designs. METHODS: In phase II, an early (24-h) outcome and adaptive sequential procedure selected one of three tenecteplase doses for phase III comparison with rt-PA. Decision rules comparing this dose to rt-PA would cause stopping for futility at phase II end, or continuation to phase III. Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale. Assuming no early termination, four interim analyses and one final analysis of 1908 patients provided an experiment-wise type I error rate of <0.05. RESULTS: Over 1,000 distribution scenarios, each involving 40,000 replications, the maximum type I error in phase III was 0.038. Inflation from the dose selection was more than offset by the one-half continuity correction in the test statistics. Inflation from repeated interim analyses was more than offset by the reduction from the clinical stopping rules for futility at the first interim analysis. LIMITATIONS: Design complexity and evolving regulatory requirements lengthened the review process. CONCLUSIONS: (1) The design was innovative and efficient. Per protocol, type I error was well controlled for the co-primary phase III hypothesis tests, and experiment-wise. (2a) Time must be allowed for communications with regulatory reviewers from first design stages. (2b) Adequate type I error control must be demonstrated. (2c) Greater clarity is needed on (i) whether this includes demonstration of type I error control if the protocol is violated and (ii) whether simulations of type I error control are acceptable. (2d) Regulatory agency concerns that protocols for futility stopping may not be followed may be allayed by submitting interim analysis results to them as these analyses occur.

Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.

BACKGROUND AND PURPOSE: Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. METHODS: The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. RESULTS: The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. CONCLUSION: This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.

Tenecteplase versus alteplase in stroke thrombolysis: An individual patient data meta-analysis of randomized controlled trials.

BACKGROUND: Tenecteplase, a modified plasminogen activator with higher fibrin specificity and longer half-life, may have advantages over alteplase in acute ischemic stroke thrombolysis. AIMS: We undertook an individual patient data meta-analysis of randomized controlled trials that compared alteplase with tenecteplase in acute stroke. METHODS: Eligible studies were identified by a MEDLINE search, and individual patient data were acquired. We compared clinical outcomes including modified Rankin Scale at three months, early neurological improvement at 24 h, intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and mortality at three months between all dose tiers of tenecteplase and alteplase. RESULTS: Three relevant studies (Haley et al., Parsons et al., and ATTEST) included 291 patients and investigated three doses of tenecteplase (0.1, 0.25, 0.4 mg/kg). There were no differences between any dose of tenecteplase and alteplase for either efficacy or safety end points. Tenecteplase 0.25 mg/kg had the greatest odds to achieve early neurological improvement (OR [95%CI] 3.3 [1.5, 7.2], p = 0.093), excellent functional outcome (modified Rankin Scale 0-1) at three months (OR [95%CI] 1.9 [0.8, 4.4], p = 0.28), with reduced odds of intracerebral hemorrhage (OR [95%CI] 0.6 [0.2, 1.8], P = 0.43) compared with alteplase. Only 19 patients were treated with tenecteplase 0.4 mg/kg, which showed increased odds of symptomatic intracerebral hemorrhage compared with alteplase (OR [95% CI] 6.2 [0.7, 56.3]). CONCLUSIONS: While no significant differences between tenecteplase and alteplase were found, point estimates suggest potentially greater efficacy of 0.25 and 0.1 mg/kg doses with no difference in symptomatic intracerebral hemorrhage, and potentially higher symptomatic intracerebral hemorrhage risk with the 0.4 mg/kg dose. Further investigation of 0.25 mg/kg tenecteplase is warranted.

A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke.

BACKGROUND AND PURPOSE: Recombinant tissue-type plasminogen activator (rtPA) is the only approved treatment in acute ischemic stroke. However, intracerebral hemorrhage (ICH) occurs in 6.4% of patients treated with rtPA and limits its use. Tenecteplase (TNK) is a modified form of rtPA, with longer half-life and greater fibrin specificity. Patients after myocardial infarction had fewer systemic hemorrhages when treated with TNK compared with rtPA. This open-label, dose-escalation safety study was conducted to develop initial experience with TNK in the treatment of ischemic stroke. METHODS: Eligible patients were treated with an intravenous bolus infusion of TNK within 3 hours of stroke onset. The dose escalation was conducted in tiers of 25 patients, starting at 0.1 mg/kg, to a planned maximum of 0.6 mg/kg. The primary endpoint was symptomatic intracranial hemorrhage within 36 hours of treatment. All patients were followed-up for 3 months. RESULTS: Eighty-eight (88) patients were treated in 4 dosing tiers. In the first 3 tiers (0.1, 0.2, 0.4 mg/kg) of 25 patients each, no symptomatic and 2 (8%), 8 (32%), and 7 (28%) asymptomatic ICHs occurred. Enrollment into the fourth tier at 0.5 mg/kg was closed after 2 of 13 patients (15%) had symptomatic and 3 (23%) had asymptomatic ICHs. Overall, modified Rankin scores at 3 months were similar to those of historical controls treated with rtPA and not significantly different between treatment groups. CONCLUSIONS: TNK doses of 0.1 to 0.4 mg/kg are safe in ischemic stroke. Future trials are needed to compare the effect of TNK on neurological outcome and safety as compared with rtPA.

Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies.

BACKGROUND AND PURPOSE: Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas trials were prospectively designed, randomized, placebo-controlled trials of gavestinel, a glycine-site antagonist and putative neuroprotectant drug administered within 6 hours of suspected ischemic or hemorrhagic stroke. Both trials reported that gavestinel was ineffective in ischemic stroke. This analysis reports the results in those with primary intracerebral hemorrhage. METHODS: The primary hypothesis was that gavestinel treatment did not alter outcome, measured at 3 months by the Barthel Index (BI), from acute intracerebral hemorrhage, based on pooled results from both trials. The BI scores were divided into 3 groups: 95 to 100 (independent), 60 to 90 (assisted independence), and 0 to 55 (dependent) or dead. RESULTS: In total, 3450 patients were randomized in GAIN International (N=1804) and GAIN Americas (N=1646). Of these, 571 were ultimately identified to have spontaneous intracerebral hematoma on baseline head computerized tomography scan. The difference in distribution of trichotomized BI scores at 3 months between gavestinel and placebo was not statistically significant (P=0.09). Serious adverse events were reported at similar rates in the 2 treatment groups. CONCLUSIONS: These observations from the combined GAIN International and GAIN Americas trials suggest that gavestinel is not of substantial benefit or harm to patients with primary intracerebral hemorrhage. These findings are similar to results previously reported in patients with ischemic stroke.

Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.

BACKGROUND: Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment. METHODS: We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage. FINDINGS: Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0.005). Odds were 2.8 (95% CI 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2) for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min in favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p<0.0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002). INTERPRETATION: The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.

Risk adjustment effect on stroke clinical trials.

BACKGROUND AND PURPOSE: The ischemic stroke population is heterogeneous. Even in balanced randomized trials, patient heterogeneity biases estimates of the treatment effect toward no effect when dichotomous end points are used. Risk adjustment statistically addresses some of the heterogeneity and can reduce bias in the treatment effect estimate. The purpose of this study was to estimate the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) tPA data set with and without adjustment for baseline differences. METHODS: Using a prespecified predictive model, we calculated unadjusted and risk-adjusted odds ratios (ORs) for favorable outcome for the Barthel Index, National Institutes of Health Stroke Scale, and Glasgow Outcome Scale for the patients in the NINDS tPA stroke trial. To assess the importance of the difference, a new sample size was calculated through the use of the risk-adjusted analysis. RESULTS: We analyzed 615 subjects. The ORs for the Barthel Index were 1.76 (unadjusted) and 2.04 (adjusted). The National Institutes of Health Stroke Scale and Glasgow Outcome Scale analyses also demonstrated increased ORs after adjustment. The estimated sample size required for the adjusted comparison was 13% smaller than the unadjusted sample. CONCLUSIONS: Risk adjustment in this data set suggests that the true treatment effect was larger than estimated by the unadjusted analysis. Stroke clinical trials should include prospective risk adjustment methodologies.

Combined clinical and imaging information as an early stroke outcome measure.

BACKGROUND AND PURPOSE: Imaging information has been proposed as a potential surrogate outcome in stroke clinical trials. The purpose of this study was to determine whether an early outcome measure combining clinical and imaging information is better than either alone in predicting 3-month outcome in acute ischemic stroke patients. METHODS: Clinical information (National Institutes of Health Stroke Scale) and imaging information (CT infarct volume), measured at 1 week from 201 patients from the Randomized Trial of Tirilazad Mesylate in Acute Stroke (RANTTAS) study, were used in a multivariable logistic regression analysis to predict excellent and devastating 3-month outcome. The combined models were compared with the infarct volume models and the clinical models. Discrimination, calibration, and change in global model chi-square were assessed. RESULTS: The combined models and models using clinical information alone had areas under the receiver operating characteristic curves that did not differ significantly (probability value = 0.092 to 0.4), ranging from 0.83 to 0.95. The imaging alone models performed less well (P<0.005) and had areas under the receiver operating characteristic curves that ranged from 0.70 to 0.80. CONCLUSIONS: The National Institutes of Health Stroke Scale at 1 week is highly predictive of 3-month outcome in ischemic stroke patients. The addition of 1-week infarct volume does not improve the accuracy of the predictive model.

Predicting outcome in ischemic stroke: external validation of predictive risk models.

BACKGROUND: Six multivariable models predicting 3-month outcome of acute ischemic stroke have been developed and internally validated previously. The purpose of this study was to externally validate the previous models in an independent data set. SUMMARY OF REPORT: We predicted outcomes for 299 patients with ischemic stroke who received placebo in the National Institute of Neurological Disorders and Stroke rt-PA trial. The model equations used 6 acute clinical variables and head CT infarct volume at 1 week as independent variables and 3-month National Institutes of Health Stroke Scale, Barthel Index, and Glasgow Outcome Scale as dependent variables. Previously developed model equations were used to forecast excellent and devastating outcome for subjects in the placebo tissue plasminogen activator data set. Area under the receiver operator characteristic curve was used to measure discrimination, and calibration charts were used to measure calibration. The validation data set patients were more severely ill (National Institutes of Health Stroke Scale and infarct volume) than the model development subjects. Area under the receiver operator characteristic curves demonstrated remarkably little degradation in the validation data set and ranged from 0.75 to 0.89. Calibration curves showed fair to good calibration. CONCLUSIONS: Our models have demonstrated excellent discrimination and acceptable calibration in an external data set. Development and validation of improved models using variables that are all available acutely are necessary.

Predicting major neurological improvement with intravenous recombinant tissue plasminogen activator treatment of stroke.

BACKGROUND AND PURPOSE: In the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study, major neurological improvement within 24 hours (MNI) occurred significantly more frequently with recombinant tissue plasminogen activator (rtPA) treatment than with placebo. We explored the relationship between MNI and 3-month favorable outcome and sought clinical predictors of MNI. METHODS: Data from 312 rtPA-treated patients from the NINDS trial were used to assess the ability of MNI to predict favorable outcome at 3 months as defined by a modified Rankin Scale score of 0 to 1. Next, a multivariable predictive model was developed for MNI within the same data set. Clinical variables examined included age, time to treatment (TTT), diabetes, pretreatment glucose, baseline National Institutes of Health Stroke Scale score, pretreatment blood pressure, history of atrial fibrillation, weight >100 kg, and a dense artery sign. Finally, this model was used to forecast into the placebo group of the NINDS trial to assess the uniqueness of the predictors in the rtPA-treated group. RESULTS: MNI had a positive predictive value and negative predictive value of 0.70 for predicting favorable 3-month outcome. Only age [odds ratio (OR), 0.68; 95% confidence interval (CI), 0.47 to 0.99] and TTT (OR, 0.56; 95% CI, 0.34 to 0.91) appear to be independently associated with MNI. The model performed only moderately well (area under the receiver-operating characteristic curve, 0.66). Age (OR, 0.67; 95% CI, 0.45 to 0.99) but not TTT was associated with MNI in the placebo group. CONCLUSIONS: MNI may be a useful surrogate for thrombolytic activity and is predictive of favorable 3-month outcome. When rates of MNI in different populations of stroke patients treated with thrombolysis are compared, adjustments for age and TTT may be necessary.

Post-emergency department management of stroke.

All stroke patients ideally should be admitted to a stroke unit in which personnel are familiar with strategies for taking care of stroke patients. Prevention of worsening cerebral ischemia by appropriate blood pressure and serum glucose management, fever control, and supplemental oxygen for hypoxemic patients is recommended. Recognition of common complications, such as aspiration pneumonia and deep venous thrombosis, highlights the need for swallowing evaluation and the use of pneumatic compression devices or subcutaneous heparin. Patients should be monitored closely for deterioration in their neurologic status and should have complications appropriately addressed. After evaluation of stroke etiology, appropriate secondary stroke prophylaxis should be selected and initiated before hospital discharge.

Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial.

BACKGROUND: The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial. METHODS: We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration. FINDINGS: Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77-0·94]; adjusted relative risk 0·88 [0·80-0·98]). INTERPRETATION: Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials. FUNDING: US National Institutes of Health and National Institute of Neurological Disorders and Stroke.

Thrombolysis in the Treatment of Acute Ischemic Stroke.

Unfortunately, intravenous alteplase, when administered within 3 hours of symptom onset, remains the only US Food and Drug Administration-approved treatment for acute ischemic stroke; it is now 7 years since its approval. Intra-arterial thrombolysis of middle cerebral and basilar artery occlusions within 6 hours of stroke onset probably is efficacious also, but the clinical trial evidence supporting this claim is less robust. The whole field of acute stroke intervention is in urgent need of more randomized, controlled clinical trials to advance management. There are several promising avenues of investigation, but clinicians must remain cautious and skeptical until convincing proof of the added benefit of new interventions is obtained.