BACKGROUND: While intravenous thrombolysis (IVT) remains the only established therapy for ischemic stroke including beyond 3 hours, there is considerable room for improvement in IVT outcomes. Non-randomized series suggested better outcomes for add-on therapies; however randomized clinical trials (RCTs) were often equivocal. One reason for these discrepancies is that imbalances in important baseline factors between treatment and control arms affect all but the largest trials and can produce misleading results. We developed techniques to identify potentially efficacious therapies by generating a pooled outcome model. Here we tested RCTs attempting to improve upon IVT against this model at each treatment arm’s baseline NIHSS and age. METHODS: We generated outcome models (mortality, mRS 0-1, mRS 0-2) pooled from the thrombolytic arms of all IV tPA RCTs with the novel feature of multi-dimensional statistical intervals. A function was iteratively fitted and individual results of IV, add-on and endovascular arms tested against this model to determine whether outcomes surpassed the + p< .05 surface (see mRS0-2 Fig.). RESULTS: Functions derived from 19 IVT RCT thrombolytic arms representing 2748 subjects were generated (Mortality: r ² =0.51; mRS0-1: r ² =0.79; 0-2: r ² =0.85). No treatment increased mortality. Three hour IVT/ultrasound with (TUCSON) or without (CLOTBUST) microspheres, the neuroprotectant Cerebrolysin and IA tPA alone (SYNTHESIS) had better functional outcomes, as did CTP-guided 6 hr. IV tenecteplase. Notably, 4.5 hour SYNTHESIS-EXPANSION (IA tPA) and IMS III (IV tPA + endovascular) did not. No extended window device showed benefit. CONCLUSION: We found that several treatments show the potential to improve outcome compared to our pooled IVT model, including 3 hour ultrasound, IA tPA and 6 hr. tenecteplase. Consistent with the cardiac experience, there remains little evidence that the 3 hour window can be extended other than by an IV thrombolytic.