Safety of Pioglitazone for Hematoma Resolution In Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) remains a devastating disease and current treatment options
lag far behind those for ischemic stroke. Current treatment efforts for ICH are targeted
towards the primary brain injury caused by the hemorrhage and growth of the hematoma. This
research targets the secondary injury caused by the persistence of toxic blood degradation
products in the brain parenchyma.

Based on preclinical work in our lab, the peroxisome proliferator activated receptor-gamma
(PPARγ), a member of the nuclear receptor superfamily, represents a possible target for the
treatment of ICH aimed at promoting hematoma absorption, limiting the pro-inflammatory
response, and protecting salvageable tissue from the damage produced by the persistence of
toxic blood degradation products.

Our primary specific aim is to assess the safety of the PPARγ agonist, pioglitazone (PIO) in
increasing doses for 3 days, when administered to patients with ICH within 24 hrs of symptom
onset. Secondarily, we aim to determine the duration of treatment of PIO for hematoma/edema
resolution in ICH. Lastly, we aim to determine whether speed of hematoma/edema resolution in
ICH represents a radiographic biological marker of activity which can be correlated with
clinical outcome and treatment effect of PIO. The ultimate purpose is to provide baseline
data on an aspect of ICH which has not been previously targeted for treatment in an effort
to develop a safe and effective treatment strategy that may be practical and applicable for
both specialized stroke centers and community hospitals.

Inclusion Criteria:

1. age 18-80 years

2. clinical presentation of spontaneous ICH

3. CT scan compatible with spontaneous ICH

4. Time to PIO treatment ≤ 24 hours from symptom onset

5. GCS ≥ 6 on initial presentation OR improvement to a GCS ≥ 6 within the time frame for
enrollment

6. Hematoma volume ≥ 5cc on initial head CT.

Exclusion Criteria:

1. Participation in another investigational trial in the previous 30 days

2. Patient will undergo surgical evacuation of ICH (ventriculostomy does NOT exclude
patient)

3. Inability to undergo neuroimaging with MRI (e.g. pacer, recent stent, inability to
lie flat)

a. If patient has mild claustrophobia or agitation amenable to mild sedation (1-2mg
lorazepam IV or 5-10mg diazepam PO), he or she may be considered for enrollment. If,
however, the patient has severe claustrophobia or agitation, he or she should not be
considered for enrollment.

4. GCS < 6

5. Baseline mRS ≥ 3

6. Primary intraventricular hemorrhage

7. ICH due to coagulopathy (PT > 15 sec or INR > 1.3, PTT > 36) or trauma

8. History of intolerance or allergy to any TZD

9. Thrombocytopenia: platelet count < 100,000

10. Clinically significant hepatic disease as demonstrated by history, clinical exam
(ascites, varices), or laboratory findings (LFTs ≥ 2x normal, coagulopathy as
described above)

11. Co-morbid conditions, which in the opinion of the investigator, are likely to
complicate therapy including but not limited to:

1. A history of NYHA class II, III, or IV CHF

2. clinically significant arrhythmia

3. end stage AIDS

12. Pregnancy as determined by a urine pregnancy test

13. Severe anemia at presentation: hemoglobin < 10 g/dL or hematocrit < 30%

14. Malignancy (history of or active)

15. Patient unlikely, in the investigator's opinion, to complete the study and return for
follow-up visits for any reason