CLEAR III

Overview

Status: Recruiting
Keywords: Intraventricular hemorrhage , Intracerebral hemorrhage , placebo , tPA , Extraventricular , Hemorrhegic Stroke
IRB Number: 00036762
Specialty: Neurology, Neurology
Sub Specialties: Neuro Critical Care, Stroke

Brief Summary

The purpose of this Phase III randomized clinical trial is to compare a policy of early extraventricular drain (EVD) use and recombinant tissue plasminogen activator (rt-PA, Cathflo® Activase® Genentech, Inc., San Francisco, CA) with EVD use and placebo (normal saline) the treatment of subjects with intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) with obstruction of the 3rd or 4th ventricles by blood. We will evaluate a population of 500 ICH subjects with intraventricular hemorrhage, representative of current clinical practice and national demographics of ICH.
 
 
Primary Aim: To determine whether early EVD placement with low-dose rt-PA improves modified Rankin Scale scores at 6 months (dichotomized Rankin 0-3 vs. 4-6) compared to subjects treated with EVD placement and placebo.
 

Primary Hypothesis: Early EVD and treatment with low-dose rt-PA can increase the percent of patients with a good functional outcome, compared to treatment with EVD and placebo by a 15% absolute difference (expressed as an odds ratio of 1.8).
 

Principal Investigator: Safdar Ansari
Department: Neurology
Co Investigator:

Contact Information

Name:Julie Martinez
Phone: 801-585-7027
Email: JULIE.MARTINEZ@UTAH.EDU

Inclusion Criteria

 

1.            Age 18-80.

2.            Symptom onset less than 24 hrs prior to diagnostic CT scan.

3.            Spontaneous ICH < 30 cc and IVH obstructing 3rd and/or 4th ventricles.

4.            ICH clot stability: ICH must be < 30 cc on initial presentation and not exceed 35 cc on 
subsequent pre-randomization stability scans. A CT scan performed 6 hours or more after IVC placement must be stable (difference is  5 cc) compared to the most previous CT scan as determined by the (AxBxC)/2 method. 
Temporary Criterion: If the clot is not stable (i.e., difference is > 5 cc), a repeat CT scan must be performed at least 12 hours later and compared to the most previous CT scan. Investigator may continue to screen every 12 hours up to 72 hours for the initial bleeding to stabilize, as long as the subject is able to be randomized within 72 hours of time of diagnostic CT scan and the clot remains < 35 cc. If the size stabilizes (i.e., enlargement < 5 cc between 2 sequential CT scans) and remains < 35 cc, the patient is eligible.

5.            IVH clot stability: The width of the lateral ventricle most compromised by blood clot must not increase by > 2 mm, allowing for movement of blood under influence of gravity. 
Temporary Criterion: If the clot is not stable (i.e., difference is > 2 mm), a repeat CT scan must be performed at least 12 hours later and compared to the most previous CT scan. Investigator may continue to screen up to 72 hours for the initial bleeding to stabilize, as long as the subject is able to be randomized within 72 hours of time of diagnostic CT scan. If the size stabilizes (i.e., enlargement  2mm between 2 sequential CT scans), the patient is eligible.

6.            Catheter tract bleeding must be less than or equal to 5 cc on CT scan for stability.
Temporary criterion: If a catheter tract hemorrhage is present on the CT scan done 6 hours after IVC placement and is > 5 cc or > 5 mm, obtain a repeat CT scan 12 hours later. This includes any bleeding at the entry site or along the catheter tract that is 5 mm in diameter seen on any CT slice or is 5 mL on more than one CT slice. If the catheter tract hemorrhage further enlarges by > 5 cc or > 5 mm as compared to the most previous CT scan, the investigator may continue to screen by repeat CT scan every 12 hours for the bleeding to stabilize, as long as the subject is able to be randomized within 72 hours of time of diagnostic CT scan. If the size stabilizes (i.e., enlargement < 5 cc or < 5 mm between 2 sequential CT scans), the patient is eligible.

7.            On stability CT scan, the 3rd and/or 4th ventricles are occluded with blood.

8.            All patients randomized will have had EVD placed, ideally using no more than 2 complete 
passes (including “soft passes” using the original trajectory), on an emergent basis as defined by the “standard of care” neurosurgical/critical care decisions of the managing physicians. If more than 2 passes are required for placement, additional stabilization of IVC site will be determined with a CT performed at 24 hours after IVC placement. 
Temporary criterion: If no IVC is in place at the time the patient is initially screened, the decision to place an IVC may occur after the patient is initially screened but an IVC must be in-place and stable at the time of randomization.

9.            Patients with primary IVH are eligible (i.e. with ICH=0).

10.        SBP < 200 mmHg sustained for the 6 h before drug administration (closest to 
randomization).
Temporary criterion: Blood pressure inclusion criteria not met when the patient is screened: Most vital signs are stabilized within the time window for enrollment.

11.        No test article may be administered until at least 12 hours after symptom onset.

12.        Able to randomize within 72 h of CT scan diagnosing IVH (provided the time of symptom 
onset to diagnostic CT does not exceed 24 h).
Temporary criterion: The 72 hour limit may be extended with approval from the Coordinating Center to allow for clot stability (ICH, IVH, catheter tract), INR stability, or other valild reason.

13.        Historical Rankin of 0 or 1. 

*The same inclusion criteria also applies to wards of the state

 

Exclusion Criteria

 

1.            Suspected (unless ruled out by angiogram or MRA/MRI) or untreated ruptured cerebral aneurysm, ruptured intracranial AVM, or tumor. Treatment of an existing aneurysm or AVM must have occurred at least 3 months before the current onset. 
Temporary criterion: This is especially important in primary IVH, when no ICH source is found. CT angiogram, angiogram, MRA/MRI, or general diagnostic study (prior to confirming patient eligibility in the protocol) is standard of care to rule out underlying etiology. If the CT angiogram, angiogram or MRA/MRI is negative, the patient is eligible. The PI must document rationale if imaging is not done.

2.            Presence of a choroid plexus vascular malformation or Moyamoya disease.

3.            Clotting disorders. Subjects requiring long-term anti-coagulation are excluded.

Temporary criterion: Reversing anticoagulation will be permitted where long-term anticoagulation is not required.

4.            Use of Dabigatran, Apixaban, and/or Rivaroxaban (or a similar medication from the same medication class) prior to symptom onset. 

5.            Platelet count < 100,000, INR > 1.4.
Temporary criterion: Low platelet counts etc. on admission can normalize within 24 hours as can an INR normalize to < 1.4.

6.            Pregnancy (positive serum or urine pregnancy test).

7.            Infratentorial hemorrhage

8.            Thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and non- 
reactive pupils. Other (supranuclear) gaze abnormalities are not an exclusion. Note: Patients 
with a posterior fossa ICH or cerebellar hematomas are ineligible.

9.            SAH at clinical presentation (an angiogram (angiogram, CTA, MRA/MRI) must be obtained 
when the diagnostic CT scan shows SAH or any hematoma location or appearance not strongly associated with hypertension. If the angiogram or other imaging does not detect a bleeding source to account for the hemorrhage, the patient is eligible for the study.) Subsequent appearance of cortical SAH secondary to clot lysis is not a dosing endpoint. 
Temporary criterion: An angiogram must be obtained when the diagnostic CT scan demonstrates subarachnoid hemorrhage or any hematoma location suggestive of aneurysm or appearing not strongly associated with hypertension. If the angiogram/imaging does not demonstrate a bleeding source that accounts for the hemorrhage, the patient is eligible for the study.

10.        ICH/IVH enlargement that cannot be stabilized in the treatment time window.
Temporary criterion: ICH enlargement during the 6-hour stabilization period (6 hours after IVC placement): It is permitted to screen up to 72 hours after diagnostic scan. If the ICH clot size stabilizes (i.e., enlarges no more than 5 cc) and does not exceed 35 cc (an ICH clot size of 35 cc allows for stabilization of a 5cc expansion for those patients at the upper limit of the ICH clot size limit), the patient is eligible.

11.        Ongoing internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts. (Patient with prior bleeding that is clinically stable for 12 h or more without any coagulopathy or bleeding disorder is eligible).

12.        Multi-focal, superficial bleeding, observed at multiple vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or site of recent surgical intervention.

13.        Prior enrollment in the study.

14.        Any other condition that the investigator believes would pose a significant hazard to the 
subject if the investigational therapy were initiated. Subjects who are not expected to survive to the day 180 visit due to co-morbidities and/or are DNR/DNI status prior to randomization are excluded. 
Temporary criterion: Although these situations are often irreversible, under 
other conditions, change can occur over 24 hours.

15.        Planned or simultaneous participation (between screening and Day-30) in another 
interventional medical investigation or clinical trial. Patients involved in observational, 
natural history, and/or epidemiological studies not involving an intervention are eligible.

16.        No subject or legal representative to give written informed consent.

*The same exclusion criteria also applies to wards of the state