title: 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.
authors.affiliation: Department of Neurology, UT Health, University of Texas Medical School-Houston, TX 77030, USA. nicole.r.gonzales@uth.tmc.edu
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Gonzales
authors.forename: Jharna
authors.initials: J
authors.lastname: Shah
authors.forename: Navdeep
authors.initials: N
authors.lastname: Sangha
authors.forename: Lenis
authors.initials: L
authors.lastname: Sosa
authors.forename: Rebecca
authors.initials: R
authors.lastname: Martinez
authors.forename: Loren
authors.initials: L
authors.lastname: Shen
authors.forename: Mallikarjunarao
authors.initials: M
authors.lastname: Kasam
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Morales
authors.forename: M Monir
authors.initials: MM
authors.lastname: Hossain
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Barreto
authors.forename: Sean I
authors.initials: SI
authors.lastname: Savitz
authors.forename: George
authors.initials: G
authors.lastname: Lopez
authors.forename: Vivek
authors.initials: V
authors.lastname: Misra
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Wu
authors.forename: Ramy
authors.initials: R
authors.lastname: El Khoury
authors.forename: Amrou
authors.initials: A
authors.lastname: Sarraj
authors.forename: Preeti
authors.initials: P
authors.lastname: Sahota
authors.forename: William
authors.initials: W
authors.lastname: Hicks
authors.forename: Indrani
authors.initials: I
authors.lastname: Acosta
authors.forename: M Rick
authors.initials: MR
authors.lastname: Sline
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Rahbar
authors.forename: Xiurong
authors.initials: X
authors.lastname: Zhao
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Aronowski
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002543:Cerebral Hemorrhage / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone