Clinical Trial on Treatment of Intraventricular Hemorrhage (CLEAR IVH)

Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (IVH)

The specific objective of this trial is to determine the lowest dose and dose frequency possible with the best pharmacokinetic and safety profile and it's ability to remove a blood clot from the ventricular system.

Study Overview

• Status: Completed
• Conditions: Intraventricular Hemorrhage
• Intervention / Treatment: Drug: tissue plasminogen activator, rt-PA (thrombolytic) (Cathflo)

Detailed Description

The purpose of this trial is to determine the efficacy and pharmacokinetics of intraventricular injections of multiple low doses of rt-PA. Sixteen subjects were already randomized to receive intraventricular injections of with 0.3 mg or 1.0 mg of rt-PA every 12 hours for up to 8 doses. Results of this stage (n=16) were then analyzed and the most effective dose of 1.0 mg was chosen to be used in the second stage (n=36) to determine the optimal frequency of dosing. We propose to test if this intervention facilitates more rapid clot resolution, complete recovery function and decreased mortality from this condition.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Centre
• Germany
  • Heidelberg, Germany, 69120
    • University of Heidelberg
• United Kingdom
  • Newcastle upon Tyne, United Kingdom, NE4 6BE
    • Newcastle General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90059
      • CR Drew Medical Center
    • Palo Alto, California, United States, 94394
      • Standford Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Via Christi Regional Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21202
      • University of Maryland Medical Systems
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis University
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • New York, New York, United States, 10029
      • Mt. Sinai Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • University of Texas HSC, San Antonio
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia, Charlottesville
    • Fairfax, Virginia, United States, 22042
      • Inova Fairfax Medical Center
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-75
2. IVC placed as standard of care using less than or equal to 2 complete passes.
3. Spontaneous ICH less than or equal to 30 cc.
4. Able to receive first dose within 48 hours of CT scan diagnosing IVH (providing the time of symptom onset to diagnostic CT does not exceed 12 hours).
5. Clot size measured on CT scan done 6 hours after IVC placement must be equal to the presentation clot size plus or minus 5 cc (as determined by the AxBxC)/2 method).
6. ON stability CT scan either the 3rd or 4th ventricles are occluded with blood (no evidence of CSF flow on CT).
7. SBP < 200 mmHg sustained for 6 hours.
8. Historical Rankin of 0 or 1.

Exclusion Criteria:

1. Suspected or untreated aneurysm or AVM (unless ruled out by angiogram or MRA/MRI).
2. Clotting disorders.
3. Patients with platelet count < 100,000, INR > 1.7, PT > 15s, or an elevated APTT.
4. Pregnancy (positive pregnancy test).
5. Infratentorial hemorrhage (i.e., parenchymal/posterior fossa hematoma; all cerebellar hematomas excluded).
6. SAH (An angiogram should be obtained when the diagnostic CT scan demonstrates subarachnoid hemorrhage or any hematoma location or appearance not strongly associated with hypertension. If the angiogram does not demonstrate a bleeding source that accounts for the hemorrhage, the patient is eligible for the study).
7. ICH enlargement during the 6-hour stabilization period (6 hour after IVC placement).
8. Internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.
9. Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or site of recent surgical intervention.
10. Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, and subacute bacterial endocarditis.
11. Prior enrollment in the study.
12. Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated.
13. Participation in another simultaneous medical investigation or trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 0.3 mg rt-PA; In stage 1 of the protocol, dose finding, subjects were randomized to either this 0.3 mg dose arm or the 1.0 mg dose arm. Subjects in this arm (0.3 mg) received up to 8 doses of 0.3 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.	Drug: tissue plasminogen activator, rt-PA (thrombolytic) (Cathflo); 0.3 mg and 1.0 mg of rt-PA (Cathflo) were administered every 12 hours (dose finding) and every 8 hours (dose frequency) via the intraventricular catheter to treat intraventricular hemorrhage.; Other Names: Activase; rt-PA; Cathflo
Active Comparator: 1.0 mg rt-PA; In stage 1 of the protocol, dose finding, subjects were randomized to either this 1.0 mg dose arm or the 0.3 mg dose arm. Subjects in this arm (1.0 mg) received up to 8 doses of 1.0 mg rt-PA every 12 hours through the intraventricular catheter to treat intraventricular hemorrhage.	Drug: tissue plasminogen activator, rt-PA (thrombolytic) (Cathflo); 0.3 mg and 1.0 mg of rt-PA (Cathflo) were administered every 12 hours (dose finding) and every 8 hours (dose frequency) via the intraventricular catheter to treat intraventricular hemorrhage.; Other Names: Activase; rt-PA; Cathflo
Experimental: 1.0 mg Rt-PA q8h; In stage 2 of the protocol, dose frequency, subjects received up to 8 doses of 1.0 mg of rt-PA (Cathflo) every 8 hours through the intraventricular catheter to treat intraventricular hemorrhage.	Drug: tissue plasminogen activator, rt-PA (thrombolytic) (Cathflo); 0.3 mg and 1.0 mg of rt-PA (Cathflo) were administered every 12 hours (dose finding) and every 8 hours (dose frequency) via the intraventricular catheter to treat intraventricular hemorrhage.; Other Names: Activase; rt-PA; Cathflo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-day Mortality	The number of subjects who died at or before the 30-day follow-up visit were determined as a measure of safety. If more than 50% of the subjects died at or before the 30-day follow-up visit, the study would have been stopped for full DSMB review.	30 days
Incidence of Bacterial Ventriculitis, Meningitis	The incidence of bacterial ventriculitis/meningitis was recorded to determine the safety of intraventricular administration of rt-PA. If 30% or more subjects experienced this event, the study would have been stopped for full DSMB review.	30 days
Rate of Symptomatic Bleeding Events	The rate of symptomatic brain bleeding events were recorded to determine the safety of intraventricular administrations of rt-PA. If 35% or more subjects experienced a symptomatic bleeding event prior to the 30-day follow-up visit, the study would have been stopped for a full DSMB review.	30-days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Daily Percentage Clot Size Resolution Over the First 3 Days	Daily IVH clot volume resolution, as a percentage of stability CT IVH volume, averaged over the first 3 days, determined by CT scans	3 days
90 Day Follow-Up Modified Rankin Scale (mRS) Score	90 day follow-up visit mRS score. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 to 6: 0. No Symptoms, 1. No Significant Disability, 2. Slight Disability, 3. Moderate Disability, 4. Moderately Severe Disability, 5. Severe Disability and 6. Dead. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)	90 days
90 Day Follow-Up Glasgow Outcome Scale (GOS) Score	90 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)	90 days
180 Day Follow-Up Modified Rankin Scale (mRS) Score	180 day follow-up visit mRS score. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 to 6: 0. No Symptoms, 1. No Significant Disability, 2. Slight Disability, 3. Moderate Disability, 4. Moderately Severe Disability, 5. Severe Disability and 6. Dead. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)	180 days
180 Day Follow-Up Glasgow Outcome Scale (GOS) Score	180 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)	180 days

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: Genentech, Inc.; FDA Office of Orphan Products Development
• Investigators: Study Chair: Daniel F Hanley, MD, Johns Hopkins University

Publications and helpful links

General Publications

• Kornbluth J, Nekoovaght-Tak S, Ullman N, Carhuapoma JR, Hanley DF, Ziai W. Early Quantification of Hematoma Hounsfield Units on Noncontrast CT in Acute Intraventricular Hemorrhage Predicts Ventricular Clearance after Intraventricular Thrombolysis. AJNR Am J Neuroradiol. 2015 Sep;36(9):1609-15. doi: 10.3174/ajnr.A4393. Epub 2015 Jul 30.
• Ziai W, Moullaali T, Nekoovaght-Tak S, Ullman N, Brooks JS, Morgan TC, Hanley DF. No exacerbation of perihematomal edema with intraventricular tissue plasminogen activator in patients with spontaneous intraventricular hemorrhage. Neurocrit Care. 2013 Jun;18(3):354-61. doi: 10.1007/s12028-013-9826-1.
• Morgan TC, Dawson J, Spengler D, Lees KR, Aldrich C, Mishra NK, Lane K, Quinn TJ, Diener-West M, Weir CJ, Higgins P, Rafferty M, Kinsley K, Ziai W, Awad I, Walters MR, Hanley D; CLEAR and VISTA Investigators. The Modified Graeb Score: an enhanced tool for intraventricular hemorrhage measurement and prediction of functional outcome. Stroke. 2013 Mar;44(3):635-41. doi: 10.1161/STROKEAHA.112.670653. Epub 2013 Jan 31.
• Webb AJ, Ullman NL, Mann S, Muschelli J, Awad IA, Hanley DF. Resolution of intraventricular hemorrhage varies by ventricular region and dose of intraventricular thrombolytic: the Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) program. Stroke. 2012 Jun;43(6):1666-8. doi: 10.1161/STROKEAHA.112.650523. Epub 2012 Apr 3.
• Ziai WC, Muschelli J, Thompson CB, Keyl PM, Lane K, Shao S, Hanley DF. Factors affecting clot lysis rates in patients with spontaneous intraventricular hemorrhage. Stroke. 2012 May;43(5):1234-9. doi: 10.1161/STROKEAHA.111.641050. Epub 2012 Mar 1.
• Herrick DB, Ziai WC, Thompson CB, Lane K, McBee NA, Hanley DF. Systemic hematologic status following intraventricular recombinant tissue-type plasminogen activator for intraventricular hemorrhage: the CLEAR IVH Study Group. Stroke. 2011 Dec;42(12):3631-3. doi: 10.1161/STROKEAHA.111.625749. Epub 2011 Sep 22.

Helpful Links

• CLEAR III Website

Study record dates

Study Major Dates

• Study Start: February 1, 2004
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: December 26, 2007
• First Submitted That Met QC Criteria: April 1, 2008
• First Posted (Estimate): April 2, 2008

Study Record Updates

• Last Update Posted (Actual): December 11, 2017
• Last Update Submitted That Met QC Criteria: November 8, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: rt-PA; Intraventricular hemorrhage (IVH)
• 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; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Tissue Plasminogen Activator; Plasminogen; Fibrinolytic Agents
• Other Study ID Numbers: IVH05; ISRCTN47341677 (Registry Identifier: ISRCTN registry)