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J Grotta

Publications and source records attributed to J Grotta.

At least 19 recordsLinked to original sources
PubMed2001

Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole.

BACKGROUND: A neuroprotective drug may be safe and effective if given very early and in combination with recombinant tissue-type plasminogen activator (rt-PA) to acute stroke patients. No clinical trial has yet tested this hypothesis. OBJECTIVE: To assess the feasibility, safety and efficacy of simultaneously combining the neuroprotective drug lubeluzole with rt-PA. METHOD: Patients who qualified for and received rt-PA within 3 h of symptom onset were randomly allocated 1:1 to lubeluzole (7.5 mg i.v. over 1 h, then continuous 5-day infusion of 10 mg/day) or placebo. Infusion of the study medication was started before the end of the 1-hour rt-PA infusion. Inclusion criteria were the same as those of the FDA-approved guidelines for rt-PA, plus National Institutes of Health Stroke Scale (NIHSS) >5 and absence of serious ventricular arrhythmia, atrioventricular block or Q-T >450 ms. EKG was continuously monitored until 48 h after treatment. The primary outcomes were adverse events, especially hemorrhage and severe arrhythmia, and functionality as determined by the Barthel Index divided into >70,0-70 and dead. RESULTS: 89 patients were randomized at 34 centers over 8 months. The study was terminated by the sponsor before the planned enrollment of 200 patients when a concurrent phase 3 trial of lubeluzole versus placebo given up to 8 h after stroke was negative. In our study, the mean NIHSS was 14.5, and the mean time from symptom onset to rt-PA was 2.5 h and to randomization to lubeluzole or placebo 3.2 h. Mortality was 26%, intracerebral hemorrhage occurred in 10% and serious adverse events in 51%. There were no differences between the two treatment groups in any of these variables, outcomes or in the Barthel Index or other measures of functionality. CONCLUSION: Combining neuroprotective drugs such as lubeluzole simultaneously with rt-PA is feasible and safe. The efficacy of this strategy, using a potentially more effective neuroprotective agent, should be evaluated in an adequately powered clinical trial.

Activities of Daily Living↗
PubMed2000

Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA stroke trial.

BACKGROUND AND PURPOSE: We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. METHODS: Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of "early activity" of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and "efficacy" and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. RESULTS: Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score </=2 at 24 hours, which provided an odds ratio of 5.4 (95% CI, 2.4 to 12.1) and a projected sample size of 58 per treatment group assuming an alpha of 0.05 (2-sided test) and a power of 80% using part I data. The top 2 and 3 of the top 5 outcome measures for detecting the longer-term efficacy of tPA also involved the NIHSS score. A Rankin score of 0 or 1 at 3 months was the third most powerful outcome measure. Outcome measures identified by CART from part I data were not as sensitive in detecting the effectiveness of tPA when applied to part II data. CONCLUSIONS: Measures using the NIHSS and a Rankin score </=1 were the most sensitive discriminators of the effectiveness of tPA in the NINDS tPA Stroke Trial compared with the other clinical and radiological measures. The outcome measures identified in this exploratory analysis (eg, NIHSS score </=2 at 24 hours) would be best used as an outcome measure in future phase II trials of recanalization begun within the first 3 hours after stroke onset, with inclusion and exclusion criteria similar to those in the NINDS tPA Stroke Trial.

Algorithms↗
PubMed2000

Lubeluzole in acute ischemic stroke treatment: A double-blind study with an 8-hour inclusion window comparing a 10-mg daily dose of lubeluzole with placebo.

BACKGROUND AND PURPOSE: This trial was a double-blind, placebo-controlled, phase III trial with an 8-hour inclusion window to assess the efficacy and safety of an intravenous loading dose of 7.5 mg followed by a daily intravenous dose of 10 mg lubeluzole for 5 days in acute ischemic stroke patients. METHODS: A total of 1786 patients were randomized: 901 to lubeluzole and 885 to placebo. Overall, 212 patients (23.5%) from the lubeluzole group and 213 (24.1%) from the placebo group discontinued the trial prematurely. In the lubeluzole group 201 patients (22.3%) discontinued because of adverse events compared with 193 patients (21.8%) in the placebo group. RESULTS: The primary population for the efficacy analysis comprised the core stroke patients (exclusion of older patients aged >75 years with severe stroke) in the 0- to 6-hour inclusion time window. The primary efficacy parameter was a 3-category functional status (Barthel Index 70 to 100/0 to 70/vegetative, dead) at week 12. In the lubeluzole group 207 patients (47.8%) were classified as mildly dependent/independent at week 12, 131 (30.3%) were moderately/severely dependent, and 95 (21.9%) were vegetative/dead. In the placebo group these numbers were 221 (54.4%), 112 (27.6%), and 73 (18.0%), respectively. Logistic regression analysis showed no statistically significant difference between the treatment groups (P:=0.162). Additionally, for none of the secondary efficacy parameters (mortality at week 12, modified Rankin score, total Barthel score) was a statistically significant difference between the lubeluzole and placebo groups obtained. There were no statistically significant differences between the 2 treatments for all treated patients, patients included within the 6- to 8-hour window, and patients with severe strokes aged >75 years. Overall, of all treated patients, 401 (22.5%) died: 203 (22.5%) in the lubeluzole group and 198 (22.4%) with placebo. Of all subjects treated, 853 (95%) on lubeluzole and 826 (93%) on placebo reported an adverse event during their treatment period or within the next 2 days after discontinuation of treatment. The most frequently observed adverse events were fever (25.9% lubeluzole; 23.4% placebo), constipation (20.2%; 19.7%), and headache (17.6%; 21.2%). Imbalances were found for atrial fibrillation (1.8% lubeluzole; 1.1% placebo) and QT prolongation (0.9%; 0.2%). CONCLUSIONS: This study failed to show an efficacy of lubeluzole in the treatment of acute stroke. On the other hand, lubeluzole treatment by the current dosage schedule was not associated with a significant safety problem.

Acute Disease↗
PubMed1999

Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial.

BACKGROUND AND PURPOSE: The purpose of this study was to test the feasibility, efficacy, and safety of combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (r-TPA) therapy for stroke within 3 hours of onset of symptoms. METHODS: This was a double-blind, randomized, placebo-controlled multi-center Phase I study of IV r-TPA or IV placebo followed by immediate cerebral arteriography and local IA administration of r-TPA by means of a microcatheter. Treatment activity was assessed by improvement on the National Institutes of Health Stroke Scale Score (NIHSSS) at 7 to 10 days. The Barthel Index, modified Rankin Scale, and the Glasgow Outcome Scale measured 3-month functional outcome. Arterial recanalization rates and their relation to total r-TPA dose and time to lysis were measured. Rates of life-threatening bleeding, intracerebral hemorrhage (ICH), or other bleeding complications assessed safety. RESULTS: Thirty-five patients were randomly assigned, 17 into the IV/IA group and 18 into the placebo/IA group. There was no difference in the 7- to 10-day or the 3-month outcomes, although there were more deaths in the IV/IA group. Clot was found in 22 of 34 patients. Recanalization was better (P=0. 03) in the IV/IA group with TIMI 3 flow in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA patients and correlated to the total dose of r-TPA (P=0.05). There was no difference in the median treatment intervals from time of onset to IV treatment (2.6 vs 2.7 hours), arteriography (3.3 vs 3.0 hours), or clot lysis (6.3 vs 5.7 hours) between the IV/IA and placebo/IA groups, respectively. A direct relation between NIHSSS and the likelihood of the presence of a clot was identified. Eight ICHs occurred; all were hemorrhagic infarctions. There were no parenchymal hematomas. Symptomatic ICH within 24 hours occurred in 1 placebo/IA patient only. Beyond 24 hours, symptomatic ICH occurred in 2 IV/IA patients only. Life-threatening bleeding complications occurred in 2 patients, both in the IV/IA group. Moderate to severe bleeding complications occurred in 2 IV/IA patients and 1 placebo/IA patient. CONCLUSIONS: This pilot study demonstrates combined IV/IA treatment is feasible and provides better recanalization, although it was not associated with improved clinical outcomes. The presence of thrombus on initial arteriography was directly related to the baseline NIHSSS. This approach is technically feasible. The numbers of symptomatic ICH were similar between the 2 groups, which suggests that this approach may be safe. Further study is needed to determine the safety and effectiveness of this new method of treatment. Such studies should address not only efficacy and safety but also the cost-benefit ratio and quality of life, given the major investment in time, personnel, and equipment required by combined IV and IA techniques.

Aged↗
PubMed1998

Neuroprotective therapy.

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. In animal models of global and focal cerebral ischemia, numerous preclinical studies have demonstrated various agents to be neuroprotective at different steps along this cascade. A wide variety of drugs has also been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They include calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilizad, anti-intercellular adhesion molecule-1 (ICAM-1) antibody, GM-1 ganglioside, clomethiazole, the sodium channel antagonist fosphenytoin, and piracetam. In the future, clinicians may have an armamentarium of treatments for acute ischemic stroke at their disposal, with a combination of agents directed at different sites in the ischemic cascade being the ultimate goal.

Brain Ischemia↗
PubMed1997

Lubeluzole treatment of acute ischemic stroke. The US and Canadian Lubeluzole Ischemic Stroke Study Group.

BACKGROUND AND PURPOSE: Lubeluzole is a novel benzothiazole compound that has shown neuroprotective activity in preclinical models of ischemic stroke. The present multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of lubeluzole in the treatment of ischemic stroke. METHODS: Seven hundred twenty-one patients with clinical symptoms of acute ischemic stroke were randomized to receive either lubeluzole (7.5 mg over 1 hour, followed by a continuous daily infusion of 10 mg for up to 5 days) or placebo. Treatment was initiated within 6 hours of symptom onset. Mortality at 12 weeks was the primary efficacy end point. Secondary efficacy end points included neurological recovery (based on the National Institutes of Health Stroke Scale [NIHSS]), functional status (based on the Barthel Index), and level of disability (based on the Rankin Scale). Safety assessments included standard and continuous electrocardiographic monitoring, physical examination, measurements of vital signs, clinical laboratory evaluation, and adverse events reports. RESULTS: The overall mortality rate at 12 weeks for lubeluzole-treated patients was 20.7% compared to 25.2% for placebo-treated patients (NS). Controlling for relevant covariates, the degree of neurological recovery (NIHSS) at week 12 significantly favored lubeluzole over placebo (P = .033). Lubeluzole treatment similarly resulted in significantly greater improvements in functional status (Barthel Index) (P = .038) and overall disability (Rankin Scale) (P = .034) after 12 weeks. A global test statistic confirmed that lubeluzole-treated patients had a more favorable clinical outcome at 12 weeks (P = .041). The safety profile of lubeluzole resembled that of placebo. CONCLUSIONS: Treatment with lubeluzole within 6 hours of the onset of ischemic stroke had a nonsignificant effect on mortality and resulted in improved clinical outcome compared with placebo, with no safety concerns.

Acute Disease↗
PubMed1996

Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t-PA Stroke Trial.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop on statistical approaches to analysis of acute stroke trials that have multiple pre-specified outcomes. An objective was to plan for statistical analysis of the NINDS t-PA Stroke Trial, a randomized, double-blind, placebo-controlled trial of recombinant tissue plasminogen activator (rt-PA) for patients with acute ischemic stroke. Treatment success was defined as a "consistent and persuasive difference" in the proportion of patients achieving favorable outcomes on the Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and National Institutes of Health Stroke Scale. The Data and Safety Monitoring Committee for the trial recommended this outcome because the committee did not believe that a positive result for a single outcome would provide sufficient evidence of efficacy. SUMMARY OF COMMENT: Workshop participants accepted the global test as a viable approach to testing the primary trial hypothesis. Clinician participants advocated categorizing outcomes as favorable/unfavorable, outcomes more clinically meaningful than continuous outcomes for evaluating a drug with potentially serious side effects. They agreed that a global test was appropriate for ischemic stroke when no single outcome is accepted. Hypothetical, special-case examples illustrate that highly correlated outcomes diminish the power of the global test. NINDS t-PA Stroke Trial data demonstrate the clinical interpretability of the global test. CONCLUSIONS: Workshop participants concluded that a global statistic should be used to test the trial's primary hypothesis accompanied by secondary tests of individual outcomes. Workshop participants recommended familiarizing the clinical/scientific community with the global approach.

Acute Disease↗