Aronowski, Jaroslaw

Background and Objectives: Peroxisome proliferator activated receptor-gamma agonists, such as pioglitazone (PIO) enhanced hematoma resolution and improved functional recovery in our animal model of intracerebral hemorrhage (ICH). We conducted a translational Phase II randomized, controlled clinical trial to determine the maximum tolerated dose (MTD) of PIO in patients with spontaneous ICH and to explore the rate of hematoma resolution and clinical outcome. Methods: Patients with spontaneous ICH within 24 hours of symptom onset were randomly allocated 1:1 to placebo or PIO. Patients received escalating doses of PIO daily for three days, followed by a 30mg maintenance dose for the duration of treatment. Duration of treatment was when 75% of the ICH had resolved as determined by serial MRI or 10 weeks of treatment, whichever occurred first. The primary safety outcome was mortality at Day 14. Secondary measures of safety include any mortality, symptomatic cerebral edema, congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Secondary measures of efficacy include hematoma resolution and clinical outcome. The MTD was determined using the Continual Reassessment Method. Results: From March 2009 to April 2013, 84 patients (42 PIO, 42 control) were enrolled into 11 dose tiers, with a planned range from 0.1-2.0 mg/kg/d. Table 1 demonstrates preliminary baseline and clinical characteristics of patients by treatment group. Overall, 2/84 patients died within 2 weeks after ICH; however mortality rate never exceeded prespecified criteria. The study will be complete in October 2013 and the treatment team remains blinded to treatment allocation. Secondary outcomes by treatment group and the MTD of PIO will be reported. Conclusions: We have completed the treatment phase of the SHRINC Trial. Long term follow-up is on-going. These results will provide the foundation for an efficacy trial evaluating PIO as a potential treatment for patients with spontaneous ICH.

AbstractCellular therapy is a promising investigational modality to enhance poststroke recovery. We conducted a single-arm, phase I clinical trial to determine the safety and feasibility of intravenous (IV) administration of autologous bone marrow mononuclear cells (MNCs) after acute ischemic stroke (AIS). Patients with moderate severity of AIS underwent bone marrow harvest followed by IV reinfusion of MNCs within 24–72 hours of onset. A target dose of 10 million cells per kilogram was chosen based on preclinical data. Patients were followed up daily during hospitalization and at 1, 3, 6, 12, and 24 months for incidence of adverse events using laboratory, clinical (12 months), and radiological (24 months) parameters. The trial was powered to detect severe adverse events (SAEs) with incidences of at least 10% and planned to enroll 30 patients. Primary outcomes were study-related SAEs and the proportion of patients successfully completing study intervention. A propensity score-based matched control group was used for the estimation of effect size (ES) for day-90 modified Rankin score (mRS). There were no study-related SAEs and, based on a futility analysis, enrolment was stopped after 25 patients. All patients successfully completed study intervention and most received the target dose. Secondary analysis estimated the ES to be a reduction of 1 point (95% confidence interval: 0.33–1.67) in median day-90 mRS for treated patients as compared with the matched control group. Bone marrow harvest and infusion of MNCs is safe and feasible in patients with AIS. The estimated ES is helpful in designing future randomized controlled trials. Stem Cells 2019;37:1481–1491