Safety and Suitability of Supplementing Early MIP Surgery (MIPS) of ICH With Pioglitazone

Study Overview
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Brief Summary
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This is an exploratory single-center prospective study of 20 subjects with primary basal ganglia ICH who will receive early MIPS in combination with perioperative pioglitazone treatment. Outcomes will be compared to matched subjects with basal ganglia ICH who undergo MIPS alone as part of the ENRICH trial. This study will take approximately two years to complete.

Detailed Description
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Study Arms: Group 1: 20 Subjects will undergo MIPS for evacuation of ICH using the BrainPath access device plus perioperative pioglitazone for 3 weeks Group 2: Subjects will undergo MIPS for evacuation of ICH using the BrainPath access device as part of the ENRICH trial (NCT02880878). These subjects will be enrolled at an ENRICH trial site independent of our Institution. Deidentified patient information from 20 subjects in this group, who will be matched to those in the ENRICH-PLUS group, will be provided to the principal investigator for comparison of outcomes. Consent for study participation will be obtained from the patient or the LAR only after fulfilling all inclusion and exclusion criteria either before or after MIPS, which will be scheduled as a standard institutional procedure outside the realm of the study. Study participants will be administered pioglitazone (15 mg tablet) either p.o. or enteral (via nasogastric tube). The first dose may be administered prior to surgery or within 3 hours of the end of surgery but must be administered within 24 hours of the index event or time last known normal (TLKN). Pioglitazone (15 mg tablet) administration will continue 3 times daily for 3 weeks, including after hospital discharge, if applicable. Following completion of pioglitazone, subjects will be followed at days 30, 90, 120 and 180 post MIPS. In addition to AE monitoring during these follow up's, a utility-weighted mRS (uw-mRS) at 180 days will serve as the primary end point.

Official Title
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A Non-Randomized Controlled Trial to Examine the Safety and Suitability of Supplementing Early Minimally Invasive Parafascicular Surgery (MIPS) for Clot Evacuation of Basal Ganglia Intracerebral Hemorrhage (ICH) With Pioglitazone

Conditions
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Intracerebral Haemorrhage, Intraventricular

Intervention / Treatment
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* Drug: Pioglitazone 15mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-80 years CT scan demonstrating an acute, spontaneous, primary basal ganglia ICH ICH volume between 30 - 80 mL as calculated by the ABC/2 method Study intervention can reasonably be initiated within 24 hours after the onset of stroke symptoms. In situations with unclear time of onset, then the onset will be considered the time that the subject was last known to be well Glasgow Coma Score (GCS) 5 - 14 Historical Modified Rankin Score 0 or 1 Consent by patient or LAR to MIS evacuation of the ICH based on best medical practice1 Time to pioglitazone treatment ≤ 24 hours from symptom onset or TLKN1 Exclusion Criteria: Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, moyamoya disease, hemorrhagic conversion of an ischemic infarct, or bleeding into a known neoplastic lesion NIHSS< 5, bilateral fixed dilated pupils, extensor motor posturing, unstable mass or evolving intracranial compartment syndrome Intraventricular extension of the hemorrhage estimated to involve >50% of either of the lateral ventricles (External ventricular drain (EVD) to treat intracranial pressure (ICP) or hydrocephalus is allowed) Primary thalamic ICH or infratentorial intraparenchymal hemorrhage including midbrain, pons or cerebellum Evidence of active bleeding involving a retroperitoneal, gastrointestinal, genitourinary, or respiratory tract site Severe kidney or liver disease (serum ALT > 2.5 x ULN) with active coagulopathy Patients requiring long-term anticoagulation that needs to be initiated < 5 days from index ICH; patient must not require Coumadin (anticoagulation) during the first 30 days (reversal of anticoagulation is permitted for medically stable patients who can safely tolerate the short-term risk of reversal) Use of anticoagulants that cannot be rapidly reversed, uncorrected coagulopathy or known clotting disorder Platelet count < 75,000 International Normalized Ratio (INR) > 1.4 after correction or inability to sustain INR ≤ 1.4 using short- and long-active procoagulants (such as, but not limited to, NovoSeven, fresh frozen plasma, vitamin K, Kcentra or Feiba) Untreatable elevated activated partial thromboplastin time (aPTT) Patients with a mechanical heart valve (presence of bioprosthetic valve(s) is permitted) Positive urine or serum pregnancy test in female subjects without documented history of surgical sterilization or is post-menopausal Participation in a concurrent interventional medical investigation or clinical trial Known life-expectancy of less than 6 months, no reasonable expectation of recovery, Do-Not-Resuscitate (DNR), or comfort measures only prior to randomization Inability or unwillingness of subject or legal guardian/representative to give written informed consent Homelessness or history of drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements intolerance or allergy to any TZD1 T2DM treated with insulin or an oral medication including Glyburide, unless the NICU physician deems it safe to replace the T2DM medication with pioglitazone1 heart failure (symptomatic or NYHA Class I-IV or newly diagnosed on admission TTE screening) patients with abnormal (>1x upper limit of normal) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: All subjects enrolled in this trial will be in the Experimental arm and receive intervention of MIPS + Pioglitazone. These patients will be compared to a dataset of subjects who have already undergone MIPS alone in a previous trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MIPS + Pioglitazone<br>20 Subjects will undergo MIPS for evacuation of ICH using the BrainPath access device plus perioperative pioglitazone for 3 weeks | Drug: Pioglitazone 15mg<br>* Study participants will be administered pioglitazone (15 mg tablet) either p.o. or enteral (via nasogastric tube). The first dose may be administered prior to surgery or within 3 hours of the end of surgery but must be administered within 24 hours of the index event or time last known normal (TLKN). Pioglitazone (15 mg tablet) administration will continue 3 times daily for 3 weeks, including after hospital discharge, if applicable.<br>|
| No Intervention: MIPS Alone<br>This trial will compare it's subjects to subjects who have previously undergone MIPS for evacuation of ICH using the BrainPath access device as part of the ENRICH trial (NCT02880878). These subjects will be enrolled at an ENRICH trial site independent of our Institution. Deidentified patient information from 20 subjects in this group, who will be matched to those in the ENRICH-PLUS group, will be provided to the principal investigator for comparison of outcomes. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Improvement - modified Rankin Scale (mRS) | Functional Improvement as determined by utility-weighted modified Rankin Scale (mRS) at 180 days. This is a scale from 0 to 6, where 0 is the best score (no symptoms) and 6 is the worst score. | 180 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as demonstrated by hematoma clearance | Determination whether there is non-inferiority or a trend toward more rapid hematoma clearance and perihematomal edema in Group 1 compared to the control arm (Group 2) as measured by serial CT scans during hospitalization residual clot on CT, perihematomal edema on CT | 7 Days | 
| Safety: Number of Participants with 30-day mortality | 30-day mortality (30 days from intervention) | 30 days | 
| Safety: hemorrhage volume | increase in hemorrhage volume between index CT and 24-hour follow-up CT | 24 Hours | 
| Safety: Number of Participants with bacterial brain infection | 30-day bacterial brain infection (30 days from intervention) | 30 Days | 
| Safety: Number of Participants with hypoglycemia | occurrences of Moderate hypoglycemia (<70 mg/dL) or Severe hypoglycemia (<50 mg/dL) requiring rescue therapy | 30, 90, 120, and 180 days | 
| Safety: Number of Participants with Drug Toxicity |  | 30, 90, 120, and 180 days | 
| Economic | Economic differential as determined by quantification of the cost per quality-adjusted life-years (QALY). QALY uses a scale of 0.00 (dead) to 1.00 (perfect health) for each health status. It is the product of duration of life and a measurement of quality of life. | 30, 90, 120, and 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pioglitazone, Basal Ganglia Intracerebral Hemorrhage (ICH), Minimally Invasive Parafascicular Surgery