Background: Intracerebral hemorrhage (ICH) remains a devastating disease and current treatment optionslag far behind those for ischemic stroke. Functional outcomes in ICH remain dismal with only 20% ofvictims being independent at 6 months [1]. To date, there are no approved therapies which improveoutcome and treatment remains mainly supportive. Current treatment efforts for ICH are targeted towardsthe primary brain injury caused by the hemorrhage and growth of the hematoma. This research targets thesecondary injury caused by the persistence of toxic blood degradation products in the brain parenchyma.Based on preclinical work in our lab, the peroxisome proliferator activated receptor-gamma (PPARv), amember of the nuclear receptor superfamily, represents a possible target for the treatment of ICH aimed atpromoting hematoma absorption, limiting the pro-inflammatory response, and protecting salvageabletissue from the damage produced by the persistence of toxic blood degradation products.Objectives: Our primary specific aim is to assess the safety of the PPARy agonist, pioglitazone (PIO) inincreasing doses from 0.1 to 2 mg/kg/d for 3 days, when administered to patients with ICH within 24 hrs ofsymptom onset. Secondarily, we aim to explore the duration of treatment of PIO for hematoma/edemaresolution in ICH. Lastly, we aim to explore whether speed of hematoma/edema resolution in ICHrepresents a radiographic biological marker of activity which can be correlated with clinical outcome andtreatment effect of PIO. The ultimate purpose is to provide baseline data on an aspect of ICH which hasnot been previously targeted for treatment in an effort to develop a safe and effective treatment strategythat may be practical and applicable for both specialized stroke centers and community hospitals.Study Design and Methods: Prospective, randomized, blinded, placebo-controlled, dose-escalation safetytrial in which patients with spontaneous ICH will be randomly allocated to placebo or treatment withescalating doses of short-term high-dose PIO (0.1 to 2.0 mg/kg/d for 3 days) followed by a lowermaintenance dose for the duration of treatment. The Continual Reassessment Method for dose-finding willbe used to determine the maximum tolerated dose of PIO. Treatment duration will be determined byexploring the time it takes for 75% of the hematoma to resolve. Hematoma and edema resolution will beevaluated with serial MR I at specified time points. Functional outcome will be evaluated at 3 and 6 monthswith the NIHSS score, Modified Rankin Scale, Barthel Index, and Stroke Impact Scale-16.ICH is a devastating disease with less than 20% of survivors being independent at 6 months. There iscurrently no approved treatment for ICH which has been shown to improve outcomes. In an effort todevelop a new treatment for ICH, this research focuses on a different aspect of ICH treatment which hasnot yet been evaluated: enhancing absorption of the blood clot with medication.Description from Appendix section:PURPOSE:Intracerebral hemorrhage (ICH) is a type of stroke caused by bleeding into the brain dueto a ruptured blood vessel. When a person develops ICH, a part of the brain does notget the oxygen and substances necessary to survive. To date, there are no approvedtherapies for this condition. The standard of care for ICH is to stop the growth of theblood clot and to control the brain swelling that happens after the injury. Therapies forICH include medications to aggressively control blood pressure, other medicationsdesigned specifically to decrease the rate of bleeding, and surgery in the appropriatepatients. Despite these efforts, there has been no treatment which has been shown toimprove outcome. Even with these treatments, only 20% of patients with ICH are able tofunction independently at 6 months. Much research remains to be done in this area.Research in the laboratory and in animal studies shows that a group of medicationscalled 'Thiazolidinediones' (TZDs) has been shown to play a positive role in controllingthe brain's response to injury. Studies evaluating TZDs in animal models of stroke havefound a protective benefit. One of the medications in this class is called pioglitazone(PIO). PIO is currently approved by the Food and Drug Administration for the treatmentof type II diabetes in adults. Our research is an investigational, off-label use of thismedication in patients with ICH.The purpose of this study is to evaluate the safety of a possible new treatment for ICH.In this study we plan to: Test the safety of PIO, Test how well patients tolerate PIO, Determine how PIO works when used with standard of care treatment in patients
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