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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Intracerebral Haemorrhage, Intraventricular
• Intervention / Treatment: Drug: Pioglitazone 15mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: J Marc Simard, MD, PhD; Phone Number: (410)328-0850; Email: msimard@som.umaryland.edu
• Study Contact Backup: Name: Kaitlyn Henry; Phone Number: (410)328-0939; Email: Khenry@som.umaryland.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Recruiting
      • University of Maryland, Baltimore
      • Contact: J Marc Simard, MD, PhD; Email: msimard@som.umaryland.edu
      • Contact: Kaitlyn Henry, Coordinator; Phone Number: 814-404-9809; Email: khenry@som.umaryland.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18-80 years
2. CT scan demonstrating an acute, spontaneous, primary basal ganglia ICH
3. ICH volume between 30 - 80 mL as calculated by the ABC/2 method
4. 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
5. Glasgow Coma Score (GCS) 5 - 14
6. Historical Modified Rankin Score 0 or 1
7. Consent by patient or LAR to MIS evacuation of the ICH based on best medical practice1
8. Time to pioglitazone treatment ≤ 24 hours from symptom onset or TLKN1

Exclusion Criteria:

1. Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, moyamoya disease, hemorrhagic conversion of an ischemic infarct, or bleeding into a known neoplastic lesion
2. NIHSS< 5, bilateral fixed dilated pupils, extensor motor posturing, unstable mass or evolving intracranial compartment syndrome
3. 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)
4. Primary thalamic ICH or infratentorial intraparenchymal hemorrhage including midbrain, pons or cerebellum
5. Evidence of active bleeding involving a retroperitoneal, gastrointestinal, genitourinary, or respiratory tract site
6. Severe kidney or liver disease (serum ALT > 2.5 x ULN) with active coagulopathy
7. 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)
8. Use of anticoagulants that cannot be rapidly reversed, uncorrected coagulopathy or known clotting disorder
9. Platelet count < 75,000
10. 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)
11. Untreatable elevated activated partial thromboplastin time (aPTT)
12. Patients with a mechanical heart valve (presence of bioprosthetic valve(s) is permitted)
13. Positive urine or serum pregnancy test in female subjects without documented history of surgical sterilization or is post-menopausal
14. Participation in a concurrent interventional medical investigation or clinical trial
15. Known life-expectancy of less than 6 months, no reasonable expectation of recovery, Do-Not-Resuscitate (DNR), or comfort measures only prior to randomization
16. Inability or unwillingness of subject or legal guardian/representative to give written informed consent
17. 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
18. intolerance or allergy to any TZD1
19. T2DM treated with insulin or an oral medication including Glyburide, unless the NICU physician deems it safe to replace the T2DM medication with pioglitazone1
20. heart failure (symptomatic or NYHA Class I-IV or newly diagnosed on admission TTE screening)
21. patients with abnormal (>1x upper limit of normal) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MIPS + Pioglitazone; 20 Subjects will undergo MIPS for evacuation of ICH using the BrainPath access device plus perioperative pioglitazone for 3 weeks	Drug: Pioglitazone 15mg; 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.
No Intervention: MIPS Alone; 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?

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

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: Nico Corporation

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2023
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 12, 2022
• First Posted (Actual): October 17, 2022

Study Record Updates

• Last Update Posted (Estimated): June 16, 2023
• Last Update Submitted That Met QC Criteria: June 14, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Pioglitazone; Basal Ganglia Intracerebral Hemorrhage (ICH); Minimally Invasive Parafascicular Surgery
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: HP-00102344

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No