The Safety of Pioglitazone for Hematoma Resolution in IntraCerebral Hemorrhage (SHRINC): A Randomised, Blinded, Phase 2, Safety Trial

Background: Peroxisome proliferator activated receptor-gamma (PPAR-γ) agonists enhanced hematoma resolution and improved functional recovery in our animal model of intracerebral haemorrhage (ICH). We conducted a translational Phase 2 randomized, controlled clinical trial to determine the maximum tolerated dose (MTD) of the PPAR-γ agonist, pioglitazone (PIO), in patients with spontaneous ICH. Methods: Patients with spontaneous ICH within 24 hours of symptom onset were randomly allocated to PIO or placebo. Patients received escalating doses of PIO daily for three days, followed by a 30 mg maintenance dose for the duration of treatment. The primary safety outcome was mortality at Day 14. Secondary measures of safety included mortality at 3 and 6 months, symptomatic cerebral oedema, hypoglycaemia, respiratory, cardiovascular, hematologic, and hepatotoxicity. Secondary measures of clinical outcomes included modified Rankin Scale (mRS) score, National Institute of Health Stroke Scale (NIHSS) score, Barthel index (BI) Stroke Impact Scale (SIS) and EuroQol (EQ) at 3 and 6 months. The MTD was determined using the Continual Reassessment Method (CRM). Findings: From March 2009 to April 2013, 84 patients (42 PIO, 42 control) were enrolled with a dose range from 7·5-135 mg/day. The primary safety outcome of death within 14 days occurred in two (2%) patients. The MTD of PIO based on CRM was 75 mg/day. Secondary measures of safety and clinical outcomes were similar between treatment groups. Interpretation: Short-term, escalating doses of PIO were tolerated in ICH patients without an increase in adverse events compared to placebo. These results provide the foundation for an efficacy trial evaluating PIO as a potential treatment for patients with spontaneous ICH. Clinical Trial Number: SHRINC was registered with ClinicalTrials.gov (NCT00827892). Funding Statement: The SHRINC Trial was funded by the National Institute of Neurological Disorders and Stroke, the American Heart Association Clinical Research Program and the National Institutes of Health/National Center for Research Resources. Declaration of Interests: The authors state: "I/We declare no competing interests." Ethics Approval Statement: IRB NUMBER: HSC-MS-08-0410, Approval to conduct this trial was sought from the Institutional Review Board (IRB) for the University of Texas Health Science Center at Houston (UTHSC-H). IRB APPROVAL DATE: 12/16/2011