Two clinical trials for investigating the expansion of the thrombolytic time window completed enrollment this year. The main objective of ReoPro Retavase Reperfusion of Stroke Safety Study -- Imaging Evaluation (ROSIE) is to identify an acceptable combination dose of fixed dose of abciximab (ReoPro) and with reteplase (Retavase) in acute stroke 3-24 hours from onset on the trinary primary outcome of Toxicity, Efficacy (complete reperfusion without toxicity at 24 hours), or Neither. A minimum rate of reperfusion of 50% of patients and maximum toxicity rate of 10% is considered acceptable. The non-MRI based companion study, ROSIE-CT, used clinical response as the criterion of efficacy. Unique design aspects utilized a Bayesian adaptive dose allocation model based on efficacy-toxicity trade-offs to assign the dose of reteplase (0, 2.5, 5, 7.5, 10U), diffusion and perfusion MRI selection criteria, and the primary efficacy outcome of reperfusion on mean transit time MRI. After interim analysis of ROSIE indicated conclusive results about the first dose level (abciximab monotherapy) and suggested that several important design modifications were desirable, we closed enrollment in both studies, have completed planned and exploratory data analyses, and have begun the design of the next clinical trial of this drug combination for the 24 hour treatment window. In total, 42 patients were enrolled and treated in ROSIE, and 11 in ROSIE-CT. Bayesian estimates of posterior mean and 90% credible interval of outcome probabilities as functions of reteplase dose, indicated that all combination doses were within the range of acceptability for toxicity, but that abciximab monotherapy (0 U reteplase) had unacceptably low response rates. Of note, a recent Phase III trial (AbESST-II) enrolled 800 patients to reach the same conclusion about futility of abciximab monotherapy that the ROSIE design statistically proved with 42 patients, demonstrating the efficiency of this approach to stroke trials. Other key observations were that the Bayesian model for dose selection performed well and responded appropriately to toxicities. There were 4 Toxic (3 symptomatic ICH) outcomes among the 53 total patients;these were at the 7.5 and 10 Units doses. Efficacy analyses indicted dose-response trends in reperfusion would be optimized by requiring a baseline perfusion deficits of >5cc and redefining reperfusion as >67% rather that as 100%. These changes as well as an enhanced Bayesian statistical model that prospectively adjusts for baseline covariates in dose allocation will be incorporated into the design of the next trial. Toward the goal in improving reperfusion and clinical outcomes in patients treated with standard iv TPA we have been conducting the Combination Anti-platelet and Anti-coagulation Treatment After Lysis of Ischemic Stroke Trial (CATALIST). This is a clinical trial to determine an acceptable dose of eptifibatide in combination with aspirin, tinzaparin (a low molecular weight heparin) in patients receiving standard iv TPA therapy. Patients may be treated with the adjunctive medicines up to 6 hours from stroke symptom onset. Two independent arms, MRI-based and non-MRI based, are being studied. In the MRI arm of the trial patients must have positive MRI evidence of hypoperfusion corresponding to symptoms of acute stroke and must be free of MRI evidence for multiple (defined as more than one) chronic micro-hemorrhages. The trial is ongoing and no results are yet available. We are investigating the potential of interferon beta-1a to protect the blood brain barrier in acute ischemic stroke and prevent hemorrhagic complications of thrombolytic therapy. The first clinical trial in this series, Recombinant human interferon beta-1a in acute ischemic stroke: a dose escalation and safety study, completed enrollment this year. The purpose of this randomized double-blind placebo-controlled sequential dose escalation, phase 1 study is to investigate the safety of IFN-beta-1a in patients with acute ischemic stroke 3-24 hours from onset and to determine the maximum tolerated dose of administration in this setting. Five dose cohorts of 5 patients (4:1 active: placebo) at 11 mcg, 22 mcg, 44 mcg, 66 mcg and 88 mcg were planned. Patients receive interferon beta 1a or placebo once daily for 7 days (dose 1 is given intravenously;doses 2-7 are injected subcutaneously). Dose escalation is continuous unless drug-related toxicity reaches a predetermined level of one dose-limiting adverse event (1 of 4 treated) within a dose cohort, in which case a second cohort of 5 patients (4:1) will be treated at that dose. The study is to be terminated at a dose level at which 2 of 4 or 3 of 8 patients on active treatment have a severe dose limiting toxicity or when all planned dose cohorts are completed. This stopping rule was reached at the 44mcg dose. Blinded data verification and analysis, including pharmacokinetic and plasma MMP-9 concentrations, are ongoing. Upon unblinding, the results will be reviewed with the DSMB and a Phase II trial in combination with tPA and using HARM as the MRI marker of drug efficacy will be designed. CLINICAL TRIAL OF MMP-9 inhibition in stroke. Our main objective is to replicate preclinical findings in a clinical population as a prerequisite for further clinical development of an MMP-9 inhibitor in acute stroke. Specifically, we will determine the effect of the MMP-9 inhibitor (chosen from preclinical work) on: BBB disruption (HARM), HT events, infarct volume, MMP- 2 and MMP- 9 plasma levels, neurological Outcome (NIH Stroke Scale, Modified Rankin Score, Barthel Index). Our hypothesis is that an MMP-9 inhibitor will reduce the incidence and severity of BBB disruption and HT events. The an MMP-9 inhibitor will be interferon-beta (Rebif) OR Minocycline (Minocin), and it will be selected based on the results of the preclinical experiments versus matching placebo. Patients will be randomized in a 1:1 ratio and stratified by alteplase-treatment status. Treatment duration will be daily for three days, at the FDA approved dose (44 mcg for IFNβ-1A;200mg for minocycline). Clinical, MRI and plasma outcomes will be assessed (relative to time of randomization) at 24 hours, 5 days (or hospital discharge if that is sooner), and 30 days. The required sample size will be driven by the ability to detect a trend in BBB disruption (HARM), since our pilot clinical data is more extensive with regards to HARM than to HT. To demonstrate a 25% reduction with 80% power (alpha=0.05, one-tailed) the study would require 54 patients per arm (n=108 total). Review of our database indicates that approximately 200 patients per year would be eligible. Enrollment within 1-2 years of the start of the trial is feasible.We estimate that approximately 20% of the sample will have received alteplase. Data Analysis Plan: All data will be collected and all images assessed blinded to treatment assignment. To investigate the primary hypothesis, a multivariate logistic regression analysis will be performed to test for an association of treatment (Active vs. Placebo) on the outcome variables, with alteplase treatment, age, and baseline NIH Stroke Scale as additional factors in the model (since these are known to be associated with the outcomes). Expected results and significance: We expect that positive effects of the drug, if present, would be most evident on BBB disruption and HT, and most evident in alteplase-treated patients. If we do replicate positive pre-clinical effects, then a larger Phase 2 safety and efficacy trial will be planned, powered to test the hypothesis of a reduction in HT events in alteplase-treated patients, with the long term goal of making thrombolytic therapy of stroke safer.
