Get access

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC)

Authors


  • Conflict of interest: None declared.
  • Funding: The design, conduct, and salary support for study personnel for SHRINC are funded by SPOTRIAS P50-NS044227 from the National Institutes of Health to the University of Texas-Houston Medical School (UT Health) Stroke Program.
  • Dr. Gonzales was also supported by the American Heart Association Clinical Research Program Award 0885050N and NIH/NCRR 1KL2 RR024149 to the University of Texas-Houston Center for Clinical and Translational Sciences.

Correspondence: Nicole R. Gonzales, Department of Neurology, University of Texas Medical School-Houston, UT Health, 6431 Fannin, MSB 7.044, Houston, TX 77030, USA.

E-mail: nicole.r.gonzales@uth.tmc.edu

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.

Get access to the full text of this article

Ancillary