Design of a Prospective, Dose-Escalation Study Evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC)

Abstract

RATIONALE : Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. AIMS : The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. STUDY DESIGN : This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. OUTCOMES : The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Novel Therapies for Intracerebral Hemorrhage

“…20 A phase II clinical trial is currently underway to test the hypothesis that pioglitazone is safe and tolerable after ICH. 21 Additional human trials with deferoxamine, …”

Hematology and Inflammatory Signaling of Intracerebral Hemorrhage

“…46 The peroxisome proliferator-activated receptor γ agonist rosiglitazone is currently undergoing a phase II clinical trial: The Safety of Pioglitazone for Hematoma Resolution In ICH (SHRINC) study, a prospective, randomized, placebo-controlled, dose-escalation safety trial. 47 A small, retrospective study investigated the efficacy/ safety of the cyclooxygenase-2 inhibitor celecoxib, in patients with ICH compared with a similar control group and reported a significant reduction in edema volume on follow-up imaging. 48 The 49 DFO was well tolerated, and not associated with an increase in serious adverse effects or mortality.…”

An Update on Inflammation in the Acute Phase of Intracerebral Hemorrhage

“…Currently, a prospective, randomized, placebo-controlled, dose-dependent clinical trial, called Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC, NCT00827892), is under way. Its purpose is to assess the effectiveness and safety of PPARg agonist rosiglitazone in clinical practice [42]. Another method for reducing the severity of inflammatory brain injury after ICH is to chelate iron [43][44][45].…”